|
Primary Arterial Hypertension
[Familial Primary Pulmonary Hypertension, Idiopathic Pulmonary Hypertension, Pulmonary Arterial Hypertension] Funded by the NIH • Developed at the University of Washington, Seattle
------------------------------------------------
Authors: James E Loyd, MD
John A Phillips, III, MD
About the Authors Initial Posting:
18 July 2002
Last Revision:
8 December 2003
From GeneReviews ------------------------------------------------- Summary
Disease characteristics. Primary pulmonary hypertension (PPH) is characterized by widespread obstruction and obliteration of the smallest pulmonary arteries. When a sufficient number of vessels are occluded, the resistance to blood flow through the lungs increases, and the right ventricle attempts to compensate by generating higher pressure to maintain pulmonary bloodflow. When the right ventricle can no longer compensate for the increased resistance, progressive heart failure ensues. Initial symptoms include dyspnea (60%), fatigue (19%), chest pain (7%), palpitation (5%), syncope (8%), or edema (3%).
The mean age at diagnosis is 36 years. Mean survival is 2.8 years. Individuals who have a family history of PPH have identical symptoms, signs, and clinical course as those with no family history of PPH. The time to diagnosis from onset of symptoms may be shorter in familial PPH, probably due to greater awareness of the disease by relatives. Diagnosis/testing. The diagnosis of PPH can be established clinically by confirming the presence of pulmonary hypertension (i.e., mean pulmonary artery pressure >25 mmHg at rest or >30 mmHg during exercise) and excluding other known causes of pulmonary hypertension. BMPR2 (chromosomal locus 2q33) is the only gene currently known to be associated with primary pulmonary hypertension. Direct molecular genetic testing of BMPR2 is available on a research basis; specific BMPR2 mutations identified through research testing may be confirmed in a clinical laboratory for patient care purposes. Linkage analysis is available clinically. Genetic counseling. Familial PPH (FPPH) is a confirmed diagnosis of PPH in a patient with a positive family history or with a causative BMPR2 mutation. Familial primary pulmonary hypertension is inherited in an autosomal dominant manner. The average penetrance of BMPR2 mutations is ~20%. If a parent has PPH, the risk for the sibs of inheriting the gene is 50%; however, because of reduced penetrance, the risk to a sib of developing PPH is ~10% (50% x ~20%). Similarly, the children of an affected individual are at 50% risk of inheriting the mutant allele; however, because of reduced penetrance, the risk to offspring of developing PPH is ~10% (50% x ~20%). Prenatal testing using molecular genetic techniques is not clinically available in the United States.
-------------------------------------------------
Diagnosis
The diagnosis of primary pulmonary hypertension (PPH) is established by clinical findings. Direct molecular genetic testing of the BMPR2 gene (chromosomal locus 2q33) is available on a research basis; specific BMPR2 mutations identified through research testing may be confirmed in a clinical laboratory for patient care purposes. Linkage analysis is available clinically. Clinical Diagnosis
The diagnosis of PPH can be established clinically, by confirming the presence of pulmonary hypertension (i.e., mean pulmonary artery pressure >25 mmHg at rest or >30 mm Hg during exercise) and excluding other known causes of pulmonary hypertension (see Differential Diagnosis) [McGoon 2001]. PPH may be suspected in patients with the following if other causative diseases are absent: Symptoms: dyspnea, fatigue, chest pain, palpitation, syncope, or edema [Rich et al 1987] Signs (abnormal findings by physical examination): Accentuation of the pulmonic component of the second heart sound
Right ventricular heave or cardiac murmur such as tricuspid regurgitation because of right ventricular dilatation
Signs of right ventricular failure such as increased venous pressure, edema, or hepatomegaly (later in the course)
Testing
PPH is diagnosed clinically by excluding other causes of pulmonary hypertension. EKG (electrocardiography). In PPH EKG may reveal changes suggestive of right atrial or right ventricular hypertrophy. In secondary pulmonary hypertension from cardiac causes, EKG may reveal other changes. Pulmonary function testing. In PPH, pulmonary function testing may show mild restriction or be normal. In secondary pulmonary hypertension, such testing may reveal evidence of parenchymal lung disease, either obstructive or restrictive. Chest radiography. In PPH, chest radiography shows normal parenchyma and may show cardiomegaly. In secondary pulmonary hypertension, it may reveal changes of other lung diseases. Perfusion lung scanning. Perfusion lung scanning is normal or mottled in PPH, or may reveal perfusion defects suggestive of pulmonary embolism. Chest computed tomography. Chest CT shows normal lung parenchyma in PPH, or high resolution imaging may show changes of interstitial lung diseases in secondary pulmonary hypertension. Echocardiography. Echocardiography is noninvasive and provides estimates of systolic pulmonary artery pressure or reveals changes of the right ventricle due to pulmonary hypertension, or both. Echocardiography is also used to screen for valvular or left ventricular disease as alternative secondary causes of pulmonary hypertension. Cardiac catherization. Clinical confirmation of the diagnosis of PPH requires cardiac catheterization to directly measure pulmonary artery pressures and to exclude other cardiac abnormalities. Lung histopathology. Lung biopsy in PPH shows occlusion of small pulmonary arteries and, in some cases, plexiform lesions, but is otherwise normal. Several pathophysiologic features may contribute to small pulmonary artery occlusion; these figures include proliferation of the intima and media of the vessel wall, vasospasm, and microthrombosis. Lung biopsy is rarely indicated for patients in whom the above tests are compatible with PPH, but on rare occasions it reveals other conditions [Palevsky et al 1989]. Molecular Genetic Testing
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by at least one US CLIA-certified laboratory or a clinical laboratory outside the US. GeneTests does not independently verify information provided by laboratories and does not warrant any aspect of a laboratory's work; listing in GeneTests does not imply that laboratories are in compliance with accreditation, licensure, or patent laws. Clinicians must communicate directly with the laboratories to verify information. —ED. Gene. BMPR2 is the only gene currently known to be associated with primary pulmonary hypertension. However, it is possible that additional loci are associated with this disorder as not all patients diagnosed with PPH possess identifiable BMPR2 mutations. Uses of testing Confirmatory diagnostic testing
Predictive testing
Test methods Sequence analysis. BMPR2 sequence analysis is available on a research basis only. Mutations in the BMPR2 gene are identified in ~50% of families with PPH [Deng et al 2000 , Lane et al 2000 , Machado et al 2001] and about 25% of patients with PPH and no family history of PPH [Thomson et al 2000].
Mutation analysis. Clinical confirmation of BMPR2 mutations identified in patients through research testing is available on a limited basis. Testing is performed only for the specific mutation identified in the research study. Table 1. Molecular Genetic Testing Used in Primary Pulmonary Hypertension Test Method Mutations Detected Mutation Detection Rate Test Availability
Sequence analysis BMPR2 mutations Positive family history: ~50% 1 Negative family history: ~25% 2 Research only
Mutation analysis Specific BMPR2 mutations identified in patients through research testing Not applicable Clinical
1. Deng et al 2000 , Lane et al 2000 , Machado et al 2001
2. Thomson et al 2000
Interpretation of sequence analysis results Known pathogenic mutation detected. The detection of a known pathogenic mutation confirms a clinical diagnosis of the disorder or a patient's predisposition to the disorder. Sequence alteration of uncertain significance detected. The clinical significance of missence mutations and single base pair changes (not resulting in an amino acid change) may be difficult to interpret. These alterations may be benign polymorphisms or, alternatively, may alter the protein structure or introduce a new splice site. The significance of these types of sequence alterations may potentially be clarified through 1) familial cosegration studies, 2) population studies to determine the frequency of the alteration in affected and unaffected individuals, or 3) protein function assays. Sequence alteration not detected. If a mutation is not identified by sequence analysis in an affected individual, three possible explanations are: 1) a disease-causing mutation is not present, 2) the mutation in the individual is not detectable due to limitations of the testing methodology, or 3) locus heterogeneity. Linkage analysis. Linkage analysis is available on a limited clinical basis and may be an option to clarify the genetic status of at-risk relatives for families in which a BMPR2 mutation has not been identified. Samples from multiple family members, including samples from at least two affected individuals, are necessary to perform linkage analysis. The accuracy of linkage analysis can be greater than 99% and is dependent on 1) the informativeness of genetic markers in the patient's family and 2) the accuracy of the clinical diagnosis of PPH in affected family members. Linkage analysis should be used with caution unless BMPR2 marker alleles can be shown to cosegregate with the PPH phenotype in a large genetically informative family. Table 2. Linkage Analysis Used in Primary Pulmonary Hypertension Test Method Accuracy Test Availability
Linkage analysis Potentially greater than 99% Clinical Genetically Related Disorders
Other phenotypes associated with mutations of BMPR2 have not been reported. Clinical Description
Primary pulmonary hypertension is caused by widespread obstruction and obliteration of the smallest pulmonary arteries. When a sufficient number of vessels are occluded, the resistance to blood flow through the lungs increases, and the right ventricle attempts to compensate by generating higher pressure to maintain pulmonary bloodflow. When the right ventricle can no longer compensate for the increased resistance, progressive heart failure ensues. Symptoms include dyspnea, fatigue, chest pain, palpitation, syncope, or edema [Rich et al 1987]. Because these symptoms are nonspecific and develop slowly, patients often attribute their first symptoms to aging or being deconditioned or overweight. Diagnosis is often delayed, in part due to low diagnostic suspicion because PPH is uncommon. Many general physicians have never seen a patient with PPH. PPH was first described clinically [Dresdale et al 1951] soon after the advent of cardiac catheterization, which permitted the direct measurement of pulmonary artery pressures. Both individuals with and without a family history of PPH have been well described. The first family with PPH was described in 1954 [Dresdale et al 1954]. More than 100 families with PPH, including one family with 18 affected individuals, are now known in the US [Newman et al 2001 , Thomas et al 2001]. PPH affects all ages, including the very young and the elderly. Females are twice as likely to be affected as males; however, disease severity and outcome are similar in males and females. The clinical characteristics and natural history of PPH were reported in a multicenter study [Rich et al 1987] before the introduction of recent new therapies. This study included 194 patients from 32 US centers, patients in whom secondary causes of pulmonary hypertension (e.g., pulmonary embolism) were excluded. Initial symptoms were dyspnea (60%), fatigue (19%), chest pain (7%), near syncope (5%), syncope (8%), palpitations (5%), and leg edema (3%). Ten percent of patients (95% of whom were female) reported Raynaud's phenomenon. The mean age at diagnosis was 36 years. Mean survival was 2.8 years.
Clinical functional capacity correlated directly with survival, such that patients who were New York Heart Association (NYHA) class IV had a mean survival of 6 months. Family history was positive in 6% of patients. Individuals who have a family history of PPH had identical symptoms, signs, and clinical course as those with no family history of PPH. The time to diagnosis from onset of symptoms may be shorter in familial PPH, probably due to greater awareness of the disease by relatives. The physiologic stress of pregnancy in a patient with PPH is significant and maternal mortality is believed to be substantial. Anecdotal reports suggest that an association may exist between PPH and pregnancy or exogenous estrogen therapy [Humbert et al 2001]. The proportion of PPH that has a genetic basis is not known, but recent evidence that 26% of patients believed to have no family history of PPH (i.e., simplex cases) had identifiable germline BMPR2 mutations [Thomson et al 2000] suggests that PPH may often be familial. Several factors may lead to under-recognition of familial PPH [Thomas et al 2001]: 1) reduced penetrance (20%) with transmission via unaffected obligate heterozygotes [Newman et al 2001], 2) inadequate family histories, and 3) incorrect diagnosis of other affected family members. It appears that subsequent generations experience earlier onset of disease in some families with PPH. Loyd et al (1995) observed that the mean age at death in subsequent generations decreased from 45±11 years to 36±13 years to 24±11 years. Prevalence
The incidence of PPH is believed to be about one to two per million population per year. Survival has improved with modern therapies [Barst 2001]; thus, so the prevalence is increasing as patients survive longer than in the past. Insufficient information is available to determine whether specific populations have different risks of PPH, but there appears to be a worldwide distribution of reports of PPH families. Differential Diagnosis
Other cardiopulmonary causes of pulmonary hypertension are far more common than PPH. Importantly, causes of secondary pulmonary hypertension need to be excluded before the diagnosis of primary pulmonary hypertension can be established. Causes of pulmonary hypertension include lung disease, pulmonary embolism, heart disease, and other [McGoon 2001 , Humbert et al 2001]. Lung disease. The advanced stages of all lung diseases may cause pulmonary hypertension. Most lung diseases that cause secondary pulmonary hypertension are identified by detection of abnormal lung sounds on physical examination, pulmonary function testing, and/or high resolution computed tomographic lung imaging. Pulmonary embolism/disease of large pulmonary vessels. Pulmonary embolism or disease of large pulmonary vessels is detected by lung perfusion scanning and confirmed by pulmonary arteriography when segmental or larger perfusion defects are present. Chronic thromboembolic pulmonary hypertension (CTEPH) is a disorder in which pulmonary emboli are not resorbed normally by fibrinolysis in contrast to that observed in the vast majority of survivors of pulmonary embolism. CTEPH is of special importance because surgical correction is possible for many patients [Fedullo et al 2001]. Heart disease. Most advanced cardiac conditions can cause pulmonary hypertension; these conditions include congenital heart disease, valvular disease, or cardiomyopathy. Heart diseases are detected by physical examination, electrocardiography, echocardiography, and cardiac catherization. Other. Other causes of pulmonary hypertension include connective tissue disease, cirrhosis, HIV infection, or treatment with appetite suppressants [Abenhaim et al 1996 , Humbert et al 2001]. Pulmonary veno-occlusive disease (PVOD) [Holcomb et al 2000] and pulmonary capillary hemangiomatosis (PCH) [Slovis et al 1998], two other disorders which are limited to the vessels of the lungs were previously classified as pathologic subsets of PPH, but are now generally accepted as distinctly different conditions. Both of these disorders are, on rare occasion, familial. Some unique families have been found to have both PPH and hereditary hemorrhagic telangiectasia ; these cases appear to be associated with mutations of another TGF beta receptor, ALK 1 [Trembath et al 2001]. Management
Management revolves around controlling the pulmonary hypertension and treatment of symptoms. The role of surveillance of at-risk family members is still poorly defined. Treatment
Referral centers specializing in diagnosis and therapy of PPH disorders are available across the US [Pulmonary Hypertension AssociationWeb site]. Treatment of pulmonary hypertension made great progress in the late 1990s [Barst 2001 , Channick & Rubin 2001 , Trulock 2001] and includes the following: Epoprostenol. A randomized controlled trial of continuous intravenous infusion of epoprostenol, an analog of prostacyclin, in patients with PPH demonstrated substantial benefit for symptoms, functional status, and survival [Barst et al 1996]. Continuous epoprostenol infusion is currently standard for treating patients with PPH who have significant functional limitations (New York Heart Assn Class III or IV). It is effective for most patients with PPH, but it is expensive and its administration is difficult because it requires continuous infusion via a portable infusion pump and a chronic central venous catheter. Dosing of epoprostenol is complicated by tachyphylaxis and a serious discontinuation response. If the infusion is stopped, patients may experience sudden worsening or even death. Calcium channel blockers. A minority of patients with PPH have a favorable long-term clinical response to oral calcium channel blockers. Such responders may be identified by a significant acute pulmonary vasodilator response assessed during cardiac catheterization. Adjunctive agents. Chronic anticoagulation therapy, with diuretics and supplemental oxygen as needed, are also used routinely in the care of patients with pulmonary hypertension. Lung transplantation. Lung transplantation is an effective treatment for many patients with PPH [Trulock 2001]. Typical age restrictions for potential transplant recipients are: 50-55 years (heart-lung transplantation); 55-60 years (bilateral lung transplantation); 60-65 years (single lung transplantation). Several problems, including insufficient availability of donor lungs, exist. Long-term survival is limited by chronic rejection for most recipients, such that mean survival after lung transplantation is about four years. Other. Several well-designed multicenter trials for PPH are recently completed or are currently in progress to identify adjunctive or alternative therapies. A recent trial demonstrated a favorable response to an oral endothelin blocker and to a prostacyclin analogue that is administered by continuous subcutaneous infusion. Avoidance of Risk Factors
Appetite suppressant medications, such as fenfluramine/phentermine and dexfenfluramine have been associated with PPH [Abenhaim et al 1996].
Cocaine, amphetamines, and related compounds causing vasocontriction have anecdotal association with pulmonary hypertension and could be risk factors [Humbert et al 2001].
Other medications that have anecdotal suggestion of risk include estrogen compounds used as oral contraceptive or replacement therapy. Anecdotal reports of association of pregnancy with onset of PPH give some concern about the risk of pregnancy; however, there is no published concensus about the best approach to birth control in patients with PPH.
The hypoxia that accompanies high altitude is associated with pulmonary vasoconstriction and pulmonary hypertension in susceptible individuals.
Patients with PPH should avoid hypoxia.
Surveillance of At-Risk Family Members
Recommendations for surveillance of asymptomatic at-risk family members are controversial. The 1998 WHO Symposium (www.WHO.org) suggested echocardiographic screening of at-risk family members every 3-5 years to enable earlier detection and treatment. However, many health insurers do not provide coverage for screening tests. The possible role of molecular genetic testing for early diagnosis of at-risk family members is yet to be established [Newman et al 2001]. However, the use of molecular genetic testing to clarify the genetic status of at-risk relatives could permit individuals in some families with PPH who do not have the mutation to safely forego clinical screening. Genetic Counseling
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal or cultural issues that individuals may face or to substitute for consultation with a genetics professional. —ED. Mode of Inheritance
Familial PPH (FPPH) is a confirmed diagnosis of PPH in a patient with a positive family history or with a causative BMPR2 mutation identified in a research study. Familial primary pulmonary hypertension is inherited in an autosomal dominant manner. Risk to Family Members
Parents of a proband. About 20% of individuals diagnosed with primary pulmonary hypertension have an affected parent. Most individuals with an identified BMPR2 mutation have inherited the mutation from a parent, but de novo mutations have been reported [Thomson et al 2000]. It is appropriate to evaluate both parents for manifestations of PPH by performing a comprehensive clinical examination and an echocardiogram. Sibs of a proband The risk to sibs of the proband depends upon the status of the parents. If a parent has PPH, the risk for the sibs of inheriting the gene is 50%; however, because of reduced penetrance [Newman et al 2001], the risk to a sib of developing PPH is ~10% (50% x ~20%). A sib known to have inherited the BMPR2 mutation has a 20% chance of developing PPH.
Offspring of a proband The children of an affected individual are at 50% risk of inheriting the mutant allele; however, because of reduced penetrance [Newman et al 2001], the risk to offspring of developing PPH is ~10% (50% x ~20%)
An offspring known to have inherited the BMPR2 mutation has a 20% chance of developing PPH.
Related Genetic Counseling Issues
Genetic counseling for family members at risk for PPH is complicated due to decreased penetrance, variable age of onset, and the inherent limitations of linkage studies, the only currently clinically available molecular genetic testing. Testing of at-risk asymptomatic adults. Testing of at-risk asymptomatic adults for PPH is available using echocardiography. Testing for cardiac changes in the absence of definite symptoms of the disease is predictive testing. At-risk asymptomatic adult family members may seek testing in order to seek early treatment and/or make personal decisions regarding reproduction, financial matters, and career planning. Those seeking testing should be counseled about possible problems they may encounter with regard to health, life, and disability insurance coverage, employment and education discrimination, and changes in social and family interaction. Other issues to consider are implications for the at-risk status of other family members. DNA banking. DNA banking is the indefinite storage of DNA, usually extracted from a peripheral blood specimen, for future use. Since it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA. DNA banking is particularly important when current molecular genetic testing does not detect all disease-causing mutations. For laboratories offering DNA banking, see DNA Banking . Prenatal Testing
Prenatal testing using molecular genetic techniques is not offered in the United States because it is not clinically available. Molecular Genetics
Information in the Molecular Genetics tables may differ from that in the text; tables may contain more recent information. —ED. Molecular Genetics of Primary Pulmonary Hypertension Gene Symbol Chromosomal Locus Protein Name
BMPR2 2q33 Bone morphogenetic protein receptor type II
Data are compiled from the following standard references: Gene symbol from HUGO; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from Swiss-Prot. OMIM Entries for Primary Pulmonary Hypertension 178600 PULMONARY HYPERTENSION, PRIMARY; PPH1
265400 PULMONARY HYPERTENSION, PRIMARY, AUTOSOMAL RECESSIVE
600799 BONE MORPHOGENETIC PROTEIN RECEPTOR, TYPE II; BMPR2
Genomic Databases for Primary Pulmonary Hypertension Gene Symbol Entrez Gene HGMD GeneCards GDB GenAtlas
BMPR2 600799 642243 BMPR2 642243 BMPR2
Normal allelic variants: The gene is comprised of 13 exons [Machado et al 2001].
Pathologic allelic variants: Over 40 unique mutations have been reported. Haploinsufficiency of BMPR2 is reported to be a molecular mechanism of PPH [Machado et al 2001].
Normal gene product: Bone morphogenetic protein receptor type II (BMPRII) with different reported protein isoforms forms a heterodimer with BMPR1 to transduce BMP signaling via SMAD proteins. BMPRII is a member of the transforming growth factor ß (TGF-ß) superfamily of cell-signaling molecules.
Abnormal gene product: 58% of reported mutations lead to truncated BMPR2 protein product.
Resources
GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. -ED. Pulmonary Hypertension Association
850 Sligo Avenue, Suite 800
Silver Spring, MD 20910
Phone: 800-748-7274; 301-565-3004
Fax: 301-565-3994
Email: candibleifer@earthlink.com
www.phassociation.org American Lung Association
1740 Broadway
New York, NY 10019
Phone: 212-315-8700
Email: infor@lungusa.org
Fact Sheet: Primary Pulmonary Hypertension (PPH) Familial Primary Pulmonary Hypertension Registry
National Familial PPH Registry References
Literature Cited
Abenhaim L, Moride Y, Brenot F, Rich S, Benichou J, Kurz X, Higenbottam T, Oakley C, Wouters E, Aubier M, Simonneau G, Begaud B (1996) Appetite-suppressant drugs and the risk of primary pulmonary hypertension. International Primary Pulmonary Hypertension Study Group. N Engl J Med 335:609-16 [Medline] Barst RJ (2001) Medical therapy of pulmonary hypertension: an overview of treatment and goals. Clin Chest Med 22:509-16 [Medline] Barst RJ, Rubin LJ, Long WA, McGoon MD, Rich S, Badesch DB, Groves BM, Tapson VF, Bourge RC, Brundage BH, et al (1996) A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary Hypertension Study Group. N Engl J Med 334:296-302 [Medline] Channick RN and Rubin LJ (2001) New and experimental therapies for pulmonary hypertension. Clin Chest Med 22:539-45 [Medline] Deng Z, Morse JH, Slager SL, Cuervo N, Moore KJ, Venetos G, Kalachikov S, Cayanis E, Fischer SG, Barst RJ, Hodge SE, Knowles JA (2000) Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet 67:737-44 [Medline] Dresdale DT, Michtom RJ, Schultz M (1954) Recent studies in primary pulmonary hypertension. Bull NY Acad Med 30:195-207 Dresdale DT, Schultz M, Michtom RJ (1951) Primary pulmonary hypertension. Clinical and hemodynamic study. Am J Med 11:686-705 Fedullo PF, Auger WR, Kerr KM, Rubin LJ (2001) Chronic thromboembolic pulmonary hypertension. N Engl J Med 345:1465-72 [Medline] Fishman AP (2001) Clinical classification of pulmonary hypertension. Clin Chest Med 22:385-92 [Medline] Holcomb BW Jr, Loyd JE, Ely EW, Johnson J, Robbins IM (2000) Pulmonary veno-occlusive disease: a case series and new observations. Chest 118:1671-9 [Medline] Humbert M, Nunes H, Sitbon O, Parent F, Herve P, Simonneau G (2001) Risk factors for pulmonary arterial hypertension. Clin Chest Med 22:459-75 [Medline] Lane KB, Machado RD, Pauciulo MW, Thomson JR, Phillips JA 3rd, Loyd JE, Nichols WC, Trembath RC (2000) Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. The International PPH Consortium. Nat Genet 26:81-4 [Medline] Loyd JE, Butler MG, Foroud TM, Conneally PM, Phillips JA 3rd, Newman JH (1995) Genetic anticipation and abnormal gender ratio at birth in familial primary pulmonary hypertension. Am J Respir Crit Care Med 152:93-7 [Medline] Machado RD, Pauciulo MW, Thomson JR, Lane KB, Morgan NV, Wheeler L, Phillips JA 3rd, Newman J, Williams D, Galie N, Manes A, McNeil K, Yacoub M, Mikhail G, Rogers P, Corris P, Humbert M, Donnai D, Martensson G, Tranebjaerg L, Loyd JE, Trembath RC, Nichols WC (2001) BMPR2 haploinsufficiency as the inherited molecular mechanism for primary pulmonary hypertension. Am J Hum Genet 68:92-102 [Medline] McGoon MD (2001) The assesment of pulmonary hypertension. Clin Chest Med 22:493-508 [Medline] Newman JH, Wheeler L, Lane KB, Loyd E, Gaddipati R, Phillips JA 3rd, Loyd JE (2001) Mutation in the gene for bone morphogenetic protein receptor II as a cause of primary pulmonary hypertension in a large kindred. N Engl J Med 345:319-24 [Medline] Nichols WC, Koller DL, Slovis B, Foroud T, Terry VH, Arnold ND, Siemieniak DR, Wheeler L, Phillips JA 3rd (1997) Localization of the gene for familial primary pulmonary hypertension to chromosome 2q31-32. Nat Genet 15:277-80 [Medline] Palevsky HI, Schloo BL, Pietra GG, Weber KT, Janicki JS, Rubin E, Fishman AP (1989) Primary pulmonary hypertension. Vascular structure, morphometry, and responsiveness to vasodilator agents. Circulation 80:1207-21 [Medline] Rich S, Dantzker DR, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, Fishman AP, Goldring RM, Groves BM, Koerner SK, et al (1987) Primary pulmonary hypertension. A national prospective study. Ann Intern Med 107:216-23 [Medline] Slovis BS, Chazova I, Loyd JE, Meyrick BO (1998) Pulmonary capillary haemangiomatosis coexistence with sinus venosus ASD: morphometric analysis and literature review. Eur Respir J 12:240-4 [Medline] Thomas AQ, Gaddipati R, Newman JH, Loyd JE (2001) Genetics of primary pulmonary hypertension. Clin Chest Med 22:477-91 [Medline] Thomson JR, Machado RD, Pauciulo MW, Morgan NV, Humbert M, Elliott GC, Ward K, Yacoub M, Mikhail G, Rogers P, Newman J, Wheeler L, Higenbottam T, Gibbs JS, Egan J, Crozier A, Peacock A, Allcock R, Corris P, Loyd JE, Trembath RC, Nichols WC (2000) Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-beta family. J Med Genet 37:741-5 [Medline] Trembath RC, Thomson JR, Machado RD, Morgan NV, Atkinson C, Winship I, Simonneau G, Galie N, Loyd JE, Humbert M, Nichols WC, Morrell NW, Berg J, Manes A, McGaughran J, Pauciulo M, Wheeler L (2001) Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia. N Engl J Med 345:325-34 [Medline]
Trulock EP (2001) Lung transplantation for primary pulmonary hypertension. Clin Chest Med 22:583-93 [Medline]
Author Information
James E Loyd, MD
Allergy, Pulmonary, and Critical Care Medicine
Vanderbilt University Medical Center
Web: www.mc.vanderbilt.edu/vumcdept/pulmonary/fpph.html John A Phillips, III, MD
Division of Medical Genetics
Vanderbilt University Medical Center
Nashville Research Registry of PPH Families
Ms Lisa Wheeler, Coordinator
Vanderbilt University
Phone: 800-288-0378 Revision History
8 December 2003 (me) Revision posted to live Web site
5 December 2003 (mr) Revision to summary wording
12 November 2003 (mr) KM edits ("sporadic" wording)
16 August 2002 (me) Internal edits
18 July 2002 (me) Review posted to live Web site
18 July 2002 (jl) Author revision
18 July 2002 (ca) PB copy edits
18 July 2002 (tk) BP edits, summary
16 July 2002 (tk) Au revisions, BP edits entered
30 June 2002 (jl) Author revisions received
19 June 2002 (ca) AA edits
17 May 2002 (ca) CD edits
14 May 2002 (ca) AA edits
8 May 2002 (tk) Reviewer edits, BP edits
17 April 2002 (tk) Entered Author revisions, BP edits
10 April 2002 (jl) Author revisions received
28 March 2002 (tk) CD, BP edits
17 March 2002 (tk) AA edits
7 March 2002 (tk) AA edits
4 March 2002 (tk) BP edits
4 February 2002 (tk) BP edits
25 January 2002 (tk) BP edits
18 January 2002 (tk) Initial conversion
14 January 2002 (jl) Original submission --------------------------------------------------
Contact
GeneTests
Copyright© 1993-2004, All Rights Reserved
University of Washington, Seattle
Terms of Use
http://www.genetests.org --------------------------------------------------
Funding Support
National Library of Medicine, NIH
National Human Genome Research Institute, NIH
Sponsoring Institution
University of Washington
Seattle, Washington
| 
