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Heritable Pulmonary Arterial Hypertension

, MD and , MD.

Author Information
, MD
Allergy, Pulmonary, and Critical Care Medicine
Vanderbilt University Medical Center
Nashville, Tennessee
, MD
Division of Medical Genetics
Vanderbilt University Medical Center
Nashville, Tennessee

Initial Posting: ; Last Revision: December 20, 2012.

Summary

Disease characteristics. Pulmonary arterial hypertension (PAH) 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 blood flow. When the right ventricle can no longer compensate for the increased resistance, progressive heart failure ensues. Initial symptoms include dyspnea (60%), fatigue (19%), syncope (8%), chest pain (7%), palpitation (5%), and edema (3%). All ages are affected, but the mean age at diagnosis is 36 years. Mean survival after diagnosis is 2.8 years; current therapy does improve clinical function but has modest effect on survival. The term heritable PAH (HPAH) includes familial PAH (PAH that occurs in two or more family members) and simplex PAH (i.e., a single occurrence in a family) when a causative mutation has been identified. Most heritable PAH (75%) is caused by a mutation in BMPR2; mutations in other genes (i.e., ACVRL1, BMPR1B, CAV1, ENG, SMAD9) are considerably less common (~1%). HPAH has identical symptoms, signs, and histology as PAH of unknown cause. The time from onset of symptoms to diagnosis may be shorter in individuals with familial PAH, possibly because of familial awareness of the disease. Three retrospective studies suggest that persons with PAH who have a BMPR2 mutation exhibit more severe disease.

Diagnosis/testing. The diagnosis of PAH can be established clinically by confirming the presence of pulmonary arterial hypertension (i.e., mean pulmonary artery pressure >25 mmHg at rest or >30 mmHg during exercise) and excluding other known causes of pulmonary hypertension (PH). The diagnosis of HPAH is confirmed by the presence of two or more family members with PAH or the identification of a responsible BMPR2 mutation in a simplex case (i.e., a single occurrence in a family).

Management. Treatment of manifestations: Referral centers specializing in PAH diagnosis and therapy are available in most regions of the US and consultation is encouraged for all patients suspected to have PAH. Continuous intravenous epoprostenol (Flolan®), the most effective therapy to date, is standard for individuals with serious or life-threatening PAH; other approved medications include treprostinil (Remodulin®) subcutaneous, treprostinil (Remodulin®) intravenous, treprostinil inhalation (Tyvaso®), inhalation iloprost (Ventavis®), bosentan (Tracleer®), ambrisentan (Letairis®), sildenafil (Revatio®), and tadalafil (Adcirca®). A small minority of individuals respond well long term to oral calcium channel blockers. Chronic anticoagulation therapy, diuretics, and supplemental oxygen are used routinely as needed. No medical therapy has been demonstrated to reverse the proliferative vascular disease which is the anatomic origin of PAH, and the effect of any therapy on long term survival overall appears marginal. Lung transplantation is effective, but long-term survival is limited by chronic rejection.

Agents/circumstances to avoid: Appetite suppressants, such as fenfluramine/phentermine, dexfenfluramine, and amfepramone (diethylpropion); cocaine, amphetamines, and related compounds causing vasoconstriction; hypoxia (including that associated with high altitude); possibly estrogen compounds used as oral contraceptives or hormone replacement therapy. Illicit drug use, especially methamphetamine, is an important cause of PAH in some regions.

Evaluation of relatives at risk: Transthoracic echocardiographic screening of at-risk family members every few years is recommended to enable earlier detection and treatment. The value of early presymptomatic diagnosis of at-risk family members is generally accepted, but yet to be established. At-risk family members who do not have the mutation known to be present in their family do not need clinical screening.

Other: Anecdotal reports of symptom onset of PAH during pregnancy raise concern about risks of pregnancy provoking onset of PAH. No consensus exists regarding the best method for birth control in women with PAH; however, recent advances in intrauterine devices suggest possible advantages to this method.

Genetic counseling. HPAH is inherited in an autosomal dominant manner, but the average penetrance of BMPR2 mutations is low, approximately 20%. If a parent of a proband has a BMPR2 mutation, the risk to each sib of inheriting the gene mutation is 50%; however, because of reduced penetrance the risk to a sib of developing PAH is approximately 10% (50% x ~20%). Similarly, each child of an affected individual is at a 50% risk of inheriting the mutant allele; however, because of reduced penetrance the risk to offspring of developing PAH is approximately 10% (50% x ~20%). Prenatal testing for pregnancies at increased risk is possible if the disease-causing mutation has been identified in the family.

Diagnosis

While the established diagnostic criteria for pulmonary arterial hypertension (PAH) have not changed, the nomenclature has changed.

Heritable PAH (HPAH) includes familial PAH (PAH that occurs in two or more family members) and simplex PAH (i.e., a single occurrence in a family) when a disease-causing mutation has been identified.

See Badesch et al [2009] for the most current information on diagnosis.

Clinical Diagnosis

The diagnosis of pulmonary arterial hypertension (PAH) may be suspected in individuals with the following if other causative diseases are absent:

  • Symptoms: dyspnea, fatigue, chest pain, palpitation, syncope, or edema.
  • Signs (abnormal findings on physical examination):
    • Accentuation of the pulmonic component of the second heart sound
    • Right ventricular heave or cardiac murmur such as tricuspid regurgitation resulting from right ventricular dilatation
    • Signs of right ventricular failure such as increased venous pressure, edema, or hepatomegaly (later in the course)

PAH can be established clinically by the following:

  • Confirmation of the presence of pulmonary arterial hypertension (i.e., mean pulmonary artery pressure >25 mmHg at rest or >30 mmHg during exercise) by right heart catheterization
  • Exclusion of other known causes of pulmonary hypertension (PH) (see Differential Diagnosis)

The presence of a BMPR2 mutation in an individual with PAH and/or the presence of PAH in another family member confirms the diagnosis of heritable PAH (HPAH).

In individuals with PAH:

  • Electrocardiography (ECG) may reveal changes suggestive of right atrial or right ventricular hypertrophy or strain. In individuals with PH associated with cardiac causes, ECG may reveal additional changes.
  • Pulmonary function testing may show mild restriction or be normal. In individuals with PH associated with parenchymal lung diseases, pulmonary function testing may reveal evidence of obstructive and/or restrictive disorders.
  • Chest radiography shows normal parenchyma and may show cardiomegaly. In those with PH associated with parenchymal lung disease, chest radiography may reveal changes of other lung diseases.
  • Perfusion lung scanning demonstrates normal distribution or is mottled, or may reveal segmental or larger perfusion defects which indicate pulmonary embolism.
  • Chest CT shows normal lung parenchyma. In individuals with PH associated with parenchymal lung disease, high-resolution imaging may show changes of interstitial lung diseases or emphysema. CT angiography has improved greatly and is noninvasive; thus it may be helpful in the evaluation of most individuals with PH. The angiographic features of chronic thromboembolic pulmonary hypertension (CTEPH) include pouching deformities and intravascular webs, which are distinctly different from the intraluminal filling defects of thrombus, as seen in acute pulmonary embolism.
  • Echocardiography, a noninvasive procedure, sometimes may provide estimates of systolic pulmonary artery pressure and/or reveal changes in the right ventricle or right atrium. Echocardiography is also used to screen for valvular or left ventricular (LV) disease as an alternative cause of PH.
  • Cardiac catheterization is used to confirm the diagnosis of PAH by directly measuring pulmonary artery pressures and excluding other cardiac abnormalities. Because increased wedge pressure resulting from LV diastolic dysfunction may be a clinically cryptic cause requiring different treatments, catheterization is recommended for all individuals with suspected PH. Challenge testing with vasodilators (i.e., inhaled nitric oxide) or fluid loading, or both, during catheterization is important to assess physiologic responses to guide appropriate therapy. Note: Challenge testing may not be available outside of referral centers.
  • Lung biopsy or histopathology at the time of transplant reveals 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: proliferation of the intima and media of the vessel wall, vasospasm, and microthrombosis. Lung biopsy is rarely indicated for individuals in whom the other tests above are compatible with PAH, but on rare occasion lung biopsy does reveal other conditions [Palevsky et al 1989].

Molecular Genetic Testing

Gene. Mutations in BMPR2 are responsible for 75% of familial PAH. Mutations are identified in 25% of individuals who represent simplex cases (i.e., a single occurrence in a family) [Thompson et al 2000].

Other loci. Mutations in other genes (i.e., ACVRL1, BMPR1B, CAV1, ENG, and SMAD9) are considerably less common (~1% each gene) [Harrison et al 2003, Shintani et al 2009, Girerd et al 2010, Austin et al 2012, Chida et al 2012]. In about 25% of families with FPAH the responsible mutation has not yet been discovered.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Heritable Pulmonary Arterial Hypertension (HPAH)

Gene SymbolProportion of HPAH Attributed to Mutations in This GeneTest MethodMutations Detected
BMPR275% 1, 2Sequence analysisSequence variants 3
Deletion / duplication analysis 4Deletion

1. BMPR2 mutations are detected in about 75% of individuals with familial PAH [Cogan et al 2006]. Of those mutations detected, 37% were point mutations in the coding region and 48% were intragenic deletion/duplications detected by MLPA or other comparable methods. Therefore, among all individuals with familial PAH, an estimated 30% of mutations are detectable by sequence analysis and 34% by deletion/duplication analysis. Twenty-five percent of simplex cases (i.e., a single occurrence in a family) have an identifiable mutation [Thompson et al 2000].

2. Cogan et al [2006]

3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.

4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a proband. To confirm the diagnosis of HPAH in a proband, it is necessary either to confirm the diagnosis of PAH in two individuals in a family or to identify by molecular genetic testing a disease-causing mutation in an individual who represents a simplex case (i.e., a single occurrence in a family).

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

The clinical characteristics and natural history of pulmonary arterial hypertension (PAH) were reported in a multicenter study [Rich et al 1987] before the introduction of effective therapies. The study, involving 32 US centers, included 194 affected individuals in whom other causes of PH (e.g., pulmonary embolism) were excluded.

Initial symptoms were dyspnea (60%), fatigue (19%), syncope (8%), chest pain (7%), near syncope (5%), palpitations (5%), and leg edema (3%). Ten percent reported Raynaud phenomenon; 95% of these individuals were female. The mean age at diagnosis was 36 years, but individuals at any age can be affected.

The clinical course varies considerably, but untreated individuals gradually deteriorate, with a mean survival of 2.8 years after diagnosis. The variability in survival across patients is broad, ranging from sudden death to decades (rare). Clinical functional capacity correlated closely with survival before the current therapies were introduced, such that individuals in New York Heart Association (NYHA) class IV had a mean survival of six months. In the current era of many medical therapies, prognosis at any point in time may be less clear, so weighing the potential benefits of current medical therapy against the incumbent risks of lung transplantation is more difficult now than in the past.

Family history was positive for PAH in 6% of individuals in large series with PAH studied in the past. Similar prevalence was reported in a national registry in France [Humbert 2010]. Individuals with a family history of PAH had symptoms, signs, and clinical course identical to those in individuals with no family history of PAH.

Because the symptoms of PAH are nonspecific and develop slowly, affected individuals often incorrectly attribute their initial symptoms to aging, poor conditioning, or overweight. Diagnosis is often delayed, in part because PAH is uncommon and thus rarely considered. The time to diagnosis from onset of symptoms may be shorter in familial PAH, perhaps because of heightened familial awareness.

PAH affects all ages, including the very young and the elderly. A recent report describes identification of a BMPR2 mutation in an 83-year-old man [Johri et al 2010].

Females are twice as likely to be affected as males; however, disease severity and outcome appear similar in males and females. Anecdotal reports suggest a possible association between familial PAH or PAH of unknown cause and pregnancy or exogenous estrogen therapy. Recent studies suggest that the female predisposition to PAH may be directly related to the effects of metabolites of estrogen [Austin et al 2009a].

The physiologic stress of pregnancy in a patient with PAH is significant and maternal mortality is believed to be substantial; however, it remains to be seen if new effective therapies may decrease this risk.

Pathophysiology. PAH is characterized by widespread obstruction and obliteration of the smallest pulmonary arteries [Runo & Loyd 2003, Hoeper & Rubin 2006]. 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 blood flow. Long-term outcome may depend on hypertrophy and compensation of the right ventricle, which also varies across individuals; however, when the heart can no longer compensate for the increased resistance, progressive heart failure ensues.

Genotype-Phenotype Correlations

About half of the known BMPR2 mutations are associated with nonsense-mediated decay (NMD) of the mutant transcript. Recent reports suggest that mutations which exhibit NMD and exhibit a haploinsufficient mechanism may have milder phenotypes than mutations which exhibit other mechanisms [Austin et al 2009b].

Penetrance

Penetrance (i.e., the presence of symptoms in an individual with a pathogenic BMPR2 mutation) is 20% [Newman et al 2001].

Female sex is the factor best demonstrated to influence penetrance: the female to male ratio in both FPAH and PAH of unknown cause is 2.5 [Austin et al 2009a] and even higher in data included in recent registries [Badesch et al 2010].

Anticipation

It appears that in some families with FPAH subsequent generations experience earlier onset of disease. Loyd et al [1995] observed that the mean age at death decreased from 45±11 years to 36±13 years to 24±11 years in three successive generations. Anticipation was also observed in a recent report of FPAH in France [Sztrymf et al 2005]. The apparent anticipation may possibly be the result of some statistical artifact or some unknown biologic phenomenon.

Nomenclature

"Primary pulmonary hypertension" was the accepted terminology from 1950 until the past decade for pulmonary arterial hypertension in the absence of known causes of pulmonary hypertension.

At the World Congress on PAH held in Venice in 2003, the term "familial PAH" (FPAH) was adopted for PAH occurring in families and the term "idiopathic pulmonary arterial hypertension" (IPAH) for persons with PAH with a negative family history and no known genetic cause [Simonneau et al 2004].

At the 2008 WHO PAH Congress, the term "heritable PAH" (HPAH) was selected to encompass both FPAH (with or without a known mutation) and "sporadic" PAH (also known as "idiopathic" IPAH) for persons who have a PAH-causing mutation but no family history of PAH [Simonneau et al 2009].

Prevalence

To date, more than 200 families with familial PAH (including one family with 36 affected individuals) are known in the US [Newman et al 2001, Thomas et al 2001], including 120 families in whom the specific BMPR2 mutation is known [Machado et al 2009].

The number of new cases of PAH of unknown cause is estimated at one or two per million population per year.

The REVEAL registry, enrolling affected individuals at 54 centers in the US between 2006 and 2007, reported on 1166 persons with IPAH (i.e., PAH of unknown cause) and 69 persons with FPAH, the latter group representing 5.6% of the total enrolled [Badesch et al 2010].

A report from France in 2008 described persons with IPAH and FPAH who were seen in the French Network of pulmonary hypertension between 1 January 2004 and 1 June 2007 and who were tested for a BMPR2 mutation [Sztrymf et al 2008]. Among a total of 233 persons with IPAH and FPAH, 38 (16.6%) reported a positive family history.

A report on PAH survival by the French Network on Pulmonary Hypertension in 2010 described enrolling 354 persons between October 2002 and October 2003, of whom 26 (7%) had a positive family history [Humbert 2010].

Insufficient information is available to determine whether specific populations have different frequencies of PAH, but the distribution of reported families with PAH (including some with causative BMPR2 mutations) is worldwide excepting Africa.

Several factors may lead to under-recognition of BMPR2-related PAH [Thomas et al 2001]:

  • Reduced penetrance (20%) with transmission via unaffected obligate heterozygotes [Newman et al 2001]
  • Inadequate family histories
  • Incorrect diagnosis of other affected family members
  • Inability of currently used test methods to detect some BMPR2 mutations, such as those occurring in its promoter region or introns

Differential Diagnosis

Other cardiopulmonary causes of pulmonary hypertension (PH) are far more common than pulmonary arterial hypertension (PAH). Importantly, causes of PH associated with related conditions need to be excluded before the diagnosis of PAH can be established. Other causes of PH include lung disease, pulmonary embolism, heart disease, connective tissue diseases, cirrhosis, and HIV infection [Badesch et al 2009].

  • Lung disease. The advanced stages of all lung diseases may cause PH. Most lung diseases that cause PH 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 imaging procedures, traditionally screening by lung perfusion scanning with confirmation by pulmonary arteriography. Although CT angiography has improved greatly, nuclear medicine perfusion scanning still has a role in screening for chronic thromboembolic pulmonary hypertension (CTEPH), a disorder in which pulmonary emboli are not resorbed normally by fibrinolysis. It is important to correctly diagnose CTEPH because surgical pulmonary thromboendarterectomy is highly effective in the appropriate medical circumstances [Piazza & Goldhaber 2011].
  • Heart disease. Most advanced cardiac conditions, including congenital heart disease, valvular disease, and cardiomyopathy, can cause PH. Heart diseases are detected by physical examination, ECG, echocardiography, and cardiac catheterization.
  • Hereditary hemorrhagic telangiectasia (HHT). Hereditary hemorrhagic telangiectasia (HHT) is characterized by the presence of multiple arteriovenous malformations (AVMs). Small AVMs (or telangiectases) close to the surface of the skin and mucous membranes often bleed after slight trauma. The most common clinical manifestation is recurrent nosebleeds (epistaxis) beginning on average at age 12 years. Approximately 25% of individuals with HHT have GI bleeding, which most commonly begins after age 50 years. AVMs often cause symptoms when they occur in the brain, liver, or lungs; complications from bleeding or shunting may be sudden and catastrophic. Pulmonary hypertension in the absence of shunt is a rare HHT manifestation, and usually occurs in individuals with mutations in ACVRL1 [Trembath et al 2001, Harrison et al 2003].

    Rarely mutations in other genes in the TGF-β family are responsible; these include ENG (encoding endoglin) and SMAD9 (previously known as SMAD8) [Shintani et al 2009].
  • Other causes of PH include connective tissue diseases, cirrhosis, HIV infection, and treatment with appetite suppressants. Pulmonary veno-occlusive disease [Holcomb et al 2000] and pulmonary capillary hemangiomatosis, two other disorders that are limited to the vessels of the lungs, were previously classified as pathologic subsets of PH, but are now generally accepted as distinct conditions. Both disorders are, on very rare occasion, familial. Anecdotal reports suggest that an association may exist between PAH and pregnancy or exogenous estrogen therapy [Austin et al 2009a].

Management

Evaluations Following Initial Diagnosis

Because pulmonary arterial hypertension (PAH) is a diagnosis of exclusion, the necessary evaluations are all completed as part of establishing the diagnosis.

Treatment of Manifestations

See McLaughlin et al [2009] for evidenced-based treatment algorithm.

Referral centers specializing in diagnosis and therapy of PAH are available across the US (see Pulmonary Hypertension Association Web site). Consultation is encouraged for all persons suspected of having PAH because of the complexity and continuing evolution of diagnosis and treatment.

Epoprostenol (Flolan®). A randomized controlled trial of continuous intravenous infusion of epoprostenol, an analog of prostacyclin, in individuals with PAH demonstrated substantial benefit in symptoms, functional status, and survival at three months. Because continuous intravenous epoprostenol appears to be the most effective therapy tested so far, it has become standard for individuals with serious or life-threatening PAH. Epoprostenol is effective for most individuals with PAH, but it is expensive and its administration is difficult because it requires continuous infusion via portable infusion pump and chronic central venous catheter. Dosing of epoprostenol is complicated by tachyphylaxis and a serious discontinuation response; if the infusion is stopped, sudden worsening or even death may occur.

Treprostinil (Remodulin®) subcutaneous. A randomized controlled trial of continuous subcutaneous infusion of treprostinil, an analog of prostacyclin, demonstrated efficacy and is now FDA approved. Pain at the subcutaneous infusion site limits dose escalation in many individuals [Simonneau et al 2002, McLaughlin et al 2003].

Treprostinil (Remodulin®) intravenous. Continuous intravenous use of treprostinil is also effective and has been FDA approved.

Treprostinil (Tyvaso®) inhalation. Inhalation of treprostinil is also effective and has been FDA approved.

Bosentan (Tracleer®). A randomized control trial of oral bosentan, a nonselective (A and B receptors) endothelin blocker, demonstrated efficacy and is now FDA approved [Rubin et al 2002].

Ambrisenan (Letairis®) is a selective endothelin blocker which demonstrated efficacy and is now FDA approved [McLaughlin et al 2009].

Sildenafil (Revatio®). A randomized trial of oral sildenafil, a phosphodiesterase inhibitor, demonstrated efficacy and is now FDA approved.

Tadalafil (Adcirca®). A randomized trial of oral tadalafil, a phosphodiesterase inhibitor, demonstrated efficacy and is now FDA approved.

Inhalation iloprost (Ventavis®). Inhalation of this prostacyclin analog circumvents the need for parenteral administration and is FDA approved.

Calcium channel blockers. A minority of individuals with PAH have a favorable long-term clinical response to oral calcium channel blockers. Such responders may be identified by a positive acute pulmonary vasodilator response (inhaled nitric oxide) assessed during cardiac catheterization. Three retrospective studies suggest that individuals with HPAH are less likely to demonstrate an acute pulmonary vasodilator response or have more severe disease than those with PAH of unknown cause [Elliott et al 2006, Rosenzweig et al 2008, Sztrymf et al 2008].

Adjunctive agents. Fluid retention may be ameliorated by diuretic therapy, hypoxemia may be helped by supplemental oxygen, and anticoagulation therapy may prevent superimposed thrombosis, especially common for indwelling catheters needed to deliver continuous infusion of a prostanoid.

Lung transplantation is an effective treatment for selected patients with PAH, but has many limitations, among them insufficient availability of donor lungs and limited long-term survival after lung transplantation for most recipients because of chronic graft rejection. Mean survival after lung transplantation is about five years.

Lung transplantation is appropriate only for patients whose lives are threatened by lung disease. Although the many effective PAH medications can improve symptoms, they do not reverse the underlying pulmonary vascular disease and it is unknown if they prolong overall survival [Humbert 2010, Macchia et al 2010]. The time span of months usually needed to assess the benefit of the many different medications or combinations of medications available can delay the decision about timing of lung transplantation.

Surveillance

See McLaughlin et al [2009] for consensus document including Reassessing Patients over Time.

The clinical course of PAH is highly variable, ranging from rapid progression to long periods of stable clinical status. The appropriate surveillance measures and timing are determined by the relative stability of the patient's clinical condition. Patients who are declining should be in frequent contact with their health care providers so that therapies may be changed or added.

Agents/Circumstances to Avoid

Appetite-suppressant medications, such as fenfluramine/phentermine, dexfenfluramine, and amfepramone (diethylpropion) have been associated with pulmonary hypertension (PH) [Abenhaim et al 1996, Abramowicz et al 2003].

Cocaine, amphetamines, and related compounds causing vasoconstriction have anecdotal association with PH and could be risk factors.

Other medications that have anecdotal suggestion of increased risk of PH include estrogen compounds used as oral contraceptives or hormone replacement therapy. Anecdotal reports associating pregnancy with onset of PH raise some concern about the risks involved with pregnancy; however, there is no published consensus regarding the best approach to birth control in women with PAH [Austin et al 2009a, Sweeney & Voelkel 2009].

The hypoxia that accompanies high altitude is associated with pulmonary vasoconstriction and PH in susceptible individuals. Individuals with PAH should avoid hypoxia.

Evaluation of Relatives at Risk

The WHO Symposia [Badesch et al 2009] recommend echocardiographic screening of at-risk family members every three to five years to enable earlier detection and treatment. However, many health insurers do not provide coverage for screening tests for asymptomatic individuals. No studies describe the frequency of compliance with the WHO recommendation.

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, in families with a known BMPR2 mutation the use of molecular genetic testing to clarify the genetic status of at-risk relatives can permit individuals who do not have the family-specific mutation to safely forego clinical screening.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

The physiologic stress of pregnancy in a woman with PAH is significant and maternal mortality is believed to be substantial; newer effective therapies may decrease this risk.

Anecdotal reports of onset of PAH with pregnancy raise concern about risks of pregnancy, but no consensus exists regarding the best approach to birth control in women with PAH [Austin et al 2009a, Sweeney & Voelkel 2009].

Therapies Under Investigation

Several investigations are actively seeking new treatment directions or compounds, and many have shown promising results in experimental models or pilot studies in affected individuals, including the following [Ghofrani et al 2009]:

  • Antiangiogenesis strategies
  • Growth factor inhibitors
  • Endothelial progenitor cells/stem cells in lung repair
  • Developing therapies against right-ventricle remodeling

Trials of combination therapy, using selected combinations of the FDA-approved therapies mentioned in Treatment of Manifestations, are in progress [Barst et al 2009].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

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, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Heritable pulmonary arterial hypertension (HPAH) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Most individuals with an identified BMPR2 mutation inherited the mutation from a parent. Because penetrance is reduced, only about 20% of those parents with the mutation are affected with PAH.
  • De novo mutations in BMPR2 have been reported [Thompson et al 2000]
  • Twenty-five percent of individuals who represent a simplex case (i.e., a single occurrence in a family) have a BMPR2 mutation [Thompson et al 2000]. These individuals may have a de novo mutation or a parent with the mutation who did not develop PAH (reduced penetrance).
  • It is appropriate to evaluate both parents for manifestations of PAH by performing a comprehensive clinical examination and echocardiogram. If a disease-causing mutation in BMPR2 has been identified in the proband, molecular genetic testing of both parents is also appropriate.

Sibs of a proband

  • The risk to sibs of the proband depends on the genetic status of the proband's parents.
  • If a parent has a BMPR2 mutation (with or without findings of PAH), the risk to the sibs of inheriting the disease-causing mutation is 50%; however, because of reduced penetrance [Newman et al 2001], the risk to a sib of developing PAH is approximately 10% (50% x ~20%)
  • A sib known to have inherited the BMPR2 mutation has a 20% chance of developing PAH.

Offspring of a proband

  • Each child of an individual with a BMPR2 mutation (with or without PAH) is at a 50% risk of inheriting the mutant allele; however, because of reduced penetrance [Newman et al 2001], the risk to offspring of developing PAH is approximately 10% (50% x ~20%)
  • An offspring known to have inherited the BMPR2 mutation has a 20% chance of developing PAH.

Other family members of a proband

  • The risk to other family members depends on the status of the proband's parents.
  • If a parent is heterozygous for a BMPR2 mutation, his or her family members are at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Genetic counseling for family members at risk for having a BMPR2 mutation and HPAH is complicated because of decreased penetrance and variable age of onset.

Because most individuals in families with FPAH already recognize the likely genetic basis for the disease, they generally welcome information that provides new understanding of its underlying cause in their family. This is in contrast to individuals who represent simplex cases in whom identification of a responsible mutation provides the first information that the disease has a genetic basis; thus, the molecular genetic test result may be received with alarm and/or disappointment because of the implications for progeny and sibs.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

Testing of at-risk asymptomatic adults for HPAH is possible using echocardiography and/or molecular genetic testing. Testing for cardiac changes in the absence of definite symptoms of the disease may detect relatives who have mild disease or who are presymptomatic.

Testing of at-risk asymptomatic adults for a BMPR2 mutation is possible using the techniques described in Molecular Genetic Testing. Such testing is not useful in predicting whether symptoms will occur, or if they do, what the age of onset, severity and type of symptoms, or rate of disease progression in asymptomatic individuals will be. When testing at-risk individuals for a BMPR2 mutation, an affected family member should be tested first to confirm the molecular diagnosis in the family.

At-risk asymptomatic adult family members may seek testing in order to plan early treatment and/or make personal decisions regarding reproduction, financial matters, and career planning. Those seeking testing should be counseled regarding possible problems that they may encounter with respect 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 is the storage of DNA (typically extracted from white blood cells) for possible future use. Because 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 of affected individuals.

Prenatal Testing

If the disease-causing mutation has been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions which (like HPAH) do not affect intellect and have treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Library of Medicine Genetics Home Reference
  • Pulmonary Hypertension Association (PHA)
    801 Roeder Road
    Suite 1000
    Silver Spring MD 20910
    Phone: 800-748-7274 (Toll-free Helpline); 301-565-3004
    Fax: 301-565-3994
    Email: PHinfo@PHAssociation.org
  • American Lung Association
    1301 Pennsylvania Avenue Northwest
    Washington DC 20004
    Phone: 800-548-8252 (Toll-free HelpLine); 800-586-4872 (toll-free); 202-785-3355
    Fax: 202-452-1805
    Email: info@lungusa.org
  • National Registry for Familial Primary Pulmonary Hypertension
    Vanderbilt University Medical Center
    1161 21st Avenue South
    T-1218 Medical Center North
    Nashville TN 37232-2650
    Phone: 800-288-0378 (toll-free)
    Fax: 615-343-7587
    Email: lisa.wheeler@vanderbilt.edu
  • REVEAL Registry
    Registry to Evaluate Early and Long Term PAH Disease Management
    Phone: 877-738-3255
    Email: info@revealregistry.com

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Heritable Pulmonary Arterial Hypertension: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Heritable Pulmonary Arterial Hypertension (View All in OMIM)

178600PULMONARY HYPERTENSION, PRIMARY, 1; PPH1
600799BONE MORPHOGENETIC PROTEIN RECEPTOR, TYPE II; BMPR2

Normal allelic variants. BMPR2 comprises 13 exons [Machado et al 2001].

Pathologic allelic variants. More than 300 unique mutations have been reported. [Machado et al 2009]. Approximately 30% of mutations localize to exon 12.

Normal gene product. Bone morphogenetic protein receptor type-2 (BMPR-2) is a member of the transforming growth factor β (TGF-β) superfamily of cell-signaling molecules. BMPR-2, with different reported protein isoforms, forms a heterodimer with BMPR1 to transduce BMP signaling via SMAD proteins. Foletta et al [2003] analyzed interactions with BMPR-2 and discovered the ability of LIMK1 to phosphorylate cofilin, which could then be alleviated by addition of BMP4. A BMPR-2 mutant containing the smallest COOH-terminal truncation described in an individual with BMPR2-related PAH failed to bind or inhibit LIMK1. This study identified the first function of the BMPR-2 tail domain and suggests that the deregulation of actin dynamics may contribute to the etiology of BMPR2-related PAH. Tctex-1, a light chain of the motor complex dynein, interacts with the cytoplasmic domain of BMPR-2 and is phosphorylated by BMPR-2 [Machado et al 2003]. BMPR-2 and Tctex-1 colocalize to endothelium and smooth muscle within the media of pulmonary arterioles, key sites of vascular remodeling in PAH. Progressively more knowledge is being obtained about BMPR2 function, but the specific pathways by which mutation leads to the proliferative vascular disease in PAH remain incompletely understood at this time.

Bmpr2 mutation mouse models develop pulmonary hypertension and recapitulate the human condition, and are valuable for preclinical trials [West et al 2008, Johnson et al 2010].

Abnormal gene product. Haploinsufficiency of BMPR-2 is reported to be a molecular mechanism of HPAH [Machado et al 2001]. Fifty-eight percent of reported BMPR2 mutations lead to truncated BMPR-2 protein product. Machado et al [2003] determined that phosphorylation of Tctex-1 is disrupted by disease-causing mutations within exon 12. Nishihara et al [2002] determined that missense mutations within the extracellular and kinase domains of BMPR-2 abrogated its signal-transducing abilities.

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

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Suggested Reading

  1. Austin ED, Loyd JE. Genetics and mediators in pulmonary arterial hypertension. Clin Chest Med. 2007;28:43–57. [PMC free article: PMC3740514] [PubMed: 17338927]
  2. Humbert M, Sitbon O, Chaouat A, Bertocchi M, Habib G, Gressin V, Yaïci A, Weitzenblum E, Cordier JF, Chabot F, Dromer C, Pison C, Reynaud-Gaubert M, Haloun A, Laurent M, Hachulla E, Cottin V, Degano B, Jaïs X, Montani D, Souza R, Simonneau G. Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era. Circulation. 2010;122:156–63. [PubMed: 20585011]
  3. Montani D, Achouh L, Dorfmuller P, Le Pavec J, Sztrymf B, Tcherakian C, Rabiller A, Haque R, Sitbon O, Jais X, Dartevelle P, Maitre S, Capron F, Musset D, Simonneau G, Humbert M. Pulmonary veno-occlusive disease: clinical, functional, radiologic, and hemodynamic characteristics and outcome of 24 cases confirmed by histology. Medicine (Baltimore). 2008;87:220–33. [PubMed: 18626305]
  4. Morrell NW, Adnot S, Archer SL, Dupuis J, Jones PL, MacLean MR, McMurtry IF, Stenmark KR, Thistlethwaite PA, Weissmann N, Yuan JX, Weir EK. Cellular and molecular basis of pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54:S20–31. [PMC free article: PMC2790324] [PubMed: 19555855]
  5. Newman JH, Phillips JA, Loyd JE. Narrative review: the enigma of pulmonary arterial hypertension: new insights from genetic studies. Ann Intern Med. 2008;148:278–83. [PubMed: 18283205]
  6. Tuder RM, Abman SH, Braun T, Capron F, Stevens T, Thistlethwaite PA, Haworth SG. Development and pathology of pulmonary hypertension. J Am Coll Cardiol. 2009;54:S3–9. [PubMed: 19555856]
  7. van Loon RL, Roofthooft MT, van Osch-Gevers M, Delhaas T, Strengers JL, Blom NA, Backx A, Berger RM. Clinical characterization of pediatric pulmonary hypertension: complex presentation and diagnosis. J Pediatr. 2009;155:176–82. [PubMed: 19524254]
  8. Wang H, Cui QQ, Sun K, Song L, Zou YB, Wang XJ, Jia L, Liu X, Gao S, Zhang CN, Hui RT. Identities and frequencies of BMPR2 mutations in Chinese patients with idiopathic pulmonary arterial hypertension. Clin Genet. 2010;77:189–92. [PubMed: 20002458]

Chapter Notes

Author Notes

Web: http://www.mc.vanderbilt.edu/vumcdept/pulmonary/fpph.html

Research Registry of PPH Families
Ms Lisa Wheeler, Coordinator
Vanderbilt University
Phone: 800-288-0378

Revision History

  • 20 December 2012 (cd) Revision: mutations in ACVRL1, BMPR1B, CAV1, ENG, and SMAD9 found in rare cases to cause FPAH
  • 29 March 2011 (me) Comprehensive update posted live
  • 15 November 2007 (cd) Revision: prenatal diagnosis available
  • 18 July 2007 (me) Comprehensive update posted to live Web site
  • 24 March 2006 (jl) Revision: duplication/deletion testing using Southern blot clinically available
  • 29 June 2005 (jl) Revision: sequence analysis clinically available
  • 2 November 2004 (me) Comprehensive update posted to live Web site
  • 8 December 2003 (jl) Revision: Summary
  • 18 July 2002 (me) Review posted to live Web site
  • 14 January 2002 (jl) Original submission
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