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Heritable Pulmonary Arterial Hypertension.

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GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018.
2002 Jul 18 [updated 2015 Jun 11].

Author information

1
Pediatric Pulmonary Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
2
Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
3
Division of Medical Genetics, Vanderbilt University Medical Center, Nashville, Tennessee

Excerpt

CLINICAL 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%), palpitations (5%), and leg 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 pathogenic variant has been identified. Most heritable PAH (75%) is caused by a pathogenic variant in BMPR2; pathogenic variants in other genes (i.e., ACVRL1, KCNK3, CAV1, SMAD9, BMPR1B) are considerably less common (1-3%). 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 pathogenic variant 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 pathogenic variant 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, the most effective therapy to date, is standard for individuals with life-threatening PAH; additional approved medications include other prostacyclin analogs, endothelin blockers, phophodiesterase inhibitors and guanylate cyclase stimulator. 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. Lung transplantation is effective, but long-term survival is limited by chronic rejection. 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. 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 by WHO guidelines to enable earlier detection and treatment. In families with a known pathogenic variant in one of the genes associated with HPAH, 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 pathogenic variant to safely forego clinical screening. However, the role of molecular genetic testing for early diagnosis of at-risk family members has yet to be established. 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 advantages to this method.

GENETIC COUNSELING:

HPAH is inherited in an autosomal dominant manner. The average penetrance of BMPR2 pathogenic variants is low, approximately 20% overall and is sex dependent. PAH develops across all ages, and the lifetime risk of developing PAH with a BMPR2 pathogenic variation in a male is 14%, whereas in a female it is 42%. (The penetrance of pathogenic variants in ACVRL1, KCNK3, CAV1, SMAD9, and BMPR1B is unknown.) If a parent of a proband has a pathogenic variant, the risk to each sib of inheriting the pathogenic variant is 50%; however, because of the reduced penetrance of BMPR1B pathogenic variants, 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 mutated allele; however, because of reduced penetrance the risk to offspring who inherit a BMPR2 pathogenic variant of developing PAH is approximately 10% (50% x ~20%). Prenatal testing for pregnancies at increased risk is possible if the pathogenic variant has been identified in the family.

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