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Hereditary pulmonary arterial hypertension
HPAH causes the blood vessels in the lungs to narrow and stiffen, making it harder for the heart to pump blood through them. This can lead to serious heart and lung complications and often affects individuals in early to mid-adulthood.
Overview
Hereditary pulmonary arterial hypertension (HPAH) is a specific form of pulmonary hypertension, a condition where blood pressure in the arteries leading from the heart to the lungs becomes abnormally high [PMID:33678732]. In HPAH, this elevated pressure occurs because the small blood vessels within the lungs narrow, thicken, and become stiff. This narrowing increases the resistance to blood flow, forcing the right side of the heart to work much harder to pump blood through the lungs. Over time, this increased workload can weaken the heart muscle.
HPAH is considered a rare condition, affecting approximately 1 to 2 individuals per million people. It is called 'hereditary' because it is caused by genetic changes passed down through families. While the condition can be serious, medical advancements have improved the outlook for many individuals.
Symptoms & clinical features
The symptoms of HPAH often develop gradually and can be non-specific, meaning they resemble those of other conditions. Early symptoms may include shortness of breath during physical activity, fatigue, and weakness. As the condition progresses, these symptoms may become more pronounced, even at rest.
Other signs and symptoms can include chest pain or discomfort, dizziness, and fainting spells (syncope), especially during exertion. Some individuals may experience swelling in the ankles, legs, or abdomen due to fluid retention. A bluish tint to the lips or skin (cyanosis) can also occur in more advanced stages, indicating reduced oxygen levels in the blood [PMID:33678732]. These symptoms result from the heart struggling to pump blood effectively and the lungs' reduced ability to oxygenate the blood.
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Affected organs
The primary organ affected in HPAH is the lung, specifically the pulmonary arteries and smaller blood vessels within the lungs. These vessels undergo structural changes, including thickening and narrowing of their walls, which increases resistance to blood flow. This increased resistance directly impacts the heart.
The right side of the heart, particularly the right ventricle, is significantly affected. It has to pump harder against the high pressure in the pulmonary arteries, leading to its enlargement and thickening (hypertrophy). Over time, this sustained strain can cause the right ventricle to weaken and eventually fail, a serious complication of HPAH. The systemic circulatory system may also show signs of fluid retention due to the heart's reduced pumping efficiency.
Risks & severity
HPAH exhibits variable penetrance, meaning that not everyone who inherits a causative genetic change will develop the condition; some individuals may carry the gene variant but remain asymptomatic [PMID:24075199]. The severity of HPAH can vary significantly among affected individuals, even within the same family. Symptoms often begin in early to mid-adulthood, typically between the ages of 20 and 40, but can appear at any age, from childhood to later in life.
Untreated HPAH can lead to severe complications, including right-sided heart failure, which is a major cause of morbidity and mortality. Regular monitoring and appropriate management are crucial to reduce the progression of the disease and improve quality of life. The prognosis has improved with the advent of targeted therapies.
Genetic causes
Hereditary pulmonary arterial hypertension is most commonly associated with pathogenic variants in the BMPR2 gene. This gene provides instructions for making bone morphogenetic protein receptor type 2, a protein found on the surface of cells, particularly in the blood vessels of the lungs [PMID:35773177]. The BMPR2 protein is part of a signalling pathway that plays a critical role in regulating cell growth, differentiation, and programmed cell death (apoptosis) in various tissues, including the pulmonary vasculature.
When a pathogenic variant occurs in the BMPR2 gene, the protein may not function correctly or may be produced in insufficient amounts. This disruption impairs the normal signalling pathway, leading to an imbalance in cell growth within the pulmonary arterial walls. This imbalance contributes to the abnormal thickening and narrowing of the blood vessels, causing the characteristic high blood pressure in the lungs observed in HPAH.
- BMPR2 bone morphogenetic protein receptor type 2
Inheritance pattern
HPAH typically follows an autosomal dominant inheritance pattern. This means that a person only needs to inherit one copy of the altered gene from one parent to have an increased risk of developing the condition. If a parent has a pathogenic variant for HPAH, there is a 50% chance with each pregnancy that their child will inherit the variant.
HPAH shows incomplete penetrance. This means that not everyone who inherits the genetic variant will develop symptoms of the disease. Therefore, even if a person inherits the altered gene, they may not develop pulmonary hypertension, or they may develop it later in life with varying severity. Family members of someone with HPAH may be offered genetic counselling to understand their risks.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Diagnosis & testing
Diagnosing HPAH typically involves a combination of clinical assessment, imaging studies, and genetic testing. If HPAH is suspected, an individual would usually be referred to a specialist centre. Initial investigations often include an echocardiogram to assess heart function and estimate pulmonary artery pressure. This may be followed by a right heart catheterisation, which is considered the gold standard for confirming the diagnosis of pulmonary hypertension and measuring its severity.
Genetic testing is crucial for confirming a diagnosis of HPAH, especially if there is a family history of the condition. In the UK, genetic testing for HPAH (often focusing on the BMPR2 gene) would be accessed through the NHS Genomic Medicine Service (GMS) via a referral from a specialist clinician, usually within an R-code framework for rare inherited diseases. A clinical geneticist or genetic counsellor would typically coordinate this process, which helps to identify the underlying genetic cause and can inform family risk assessments.
Management & lifestyle
While there is currently no cure for HPAH, management focuses on alleviating symptoms, improving quality of life, and slowing disease progression. Treatment strategies are highly individualised and are typically overseen by specialist pulmonary hypertension centres within the NHS. Medications, such as vasodilators, are often prescribed to relax and widen the narrowed pulmonary arteries, thereby reducing the pressure and easing the heart's workload.
Regular monitoring of heart and lung function is essential. Lifestyle adjustments, such as avoiding high altitudes, strenuous physical activity, and certain medications, may be advised. In some cases, advanced treatments like oxygen therapy or, rarely, lung transplantation, may be considered for severe disease. Genetic counsellors can provide support and information regarding the hereditary aspects of the condition and implications for family planning.
UK care pathway
In the UK, individuals suspected of having or diagnosed with HPAH typically enter a care pathway through the NHS Genomic Medicine Service (GMS). This usually involves referral to a specialist pulmonary hypertension centre. Genetic testing, often under an R-code, would be coordinated by a clinical genetics service, usually following specialist clinical assessment. Genetic counsellors play a vital role in explaining genetic test results, inheritance patterns, and family implications, offering support and guidance throughout the process.
Frequently asked questions
What does 'autosomal dominant' inheritance mean for HPAH?
Autosomal dominant inheritance means that a person only needs to inherit one altered copy of the gene, typically from one parent, to have an increased chance of developing the condition. If a parent has the genetic change, there is a 50% chance their child will inherit it with each pregnancy.
Can HPAH skip a generation?
Yes, HPAH can appear to skip a generation due to a concept called 'incomplete penetrance'. This means that not everyone who inherits the genetic change will develop symptoms of the condition, or they may develop very mild symptoms that go unnoticed.
Is there a cure for HPAH?
Currently, there is no cure for HPAH. However, there are various treatments available that can help manage symptoms, improve quality of life, and slow the progression of the disease. These treatments are typically administered at specialist centres.
What kind of doctor treats HPAH?
HPAH is typically managed by a team of specialists, often at a dedicated pulmonary hypertension centre. This team may include cardiologists (heart specialists), pulmonologists (lung specialists), and clinical geneticists, along with specialist nurses and genetic counsellors.
How common is Hereditary Pulmonary Arterial Hypertension?
HPAH is considered a rare condition, affecting approximately 1 to 2 people out of every million in the population.
References
- Ivy DD, Abman SH, Barst RJ. Pediatric pulmonary hypertension. Journal of the American College of Cardiology. 2013. PMID: 24355636
- Matsubara H, Ogawa A. Treatment of idiopathic/hereditary pulmonary arterial hypertension. Journal of cardiology. 2014. PMID: 25082294
- Brenner L, Chung WK. Clinical and molecular genetic features of hereditary pulmonary arterial hypertension. Comprehensive physiology. 2011. PMID: 23733703
- Santos-Ferreira CA, Abreu MT, Marques CI. Micro-RNA Analysis in Pulmonary Arterial Hypertension: Current Knowledge and Challenges. JACC. Basic to translational science. 2020. PMID: 33294743
- Hamid R, Loyd J. Pre-implantation genetic testing for hereditary pulmonary arterial hypertension: promise and caution. The European respiratory journal. 2012. PMID: 22654004
- Ge X, Zhu T, Zhang X. Gender differences in pulmonary arterial hypertension patients with BMPR2 mutation: a meta-analysis. Respiratory research. 2020. PMID: 32028950
- Zhang X, Zhang C, Li Q. TGF-β receptor mutations and clinical prognosis in Chinese pediatric patients with idiopathic/hereditary pulmonary arterial hypertension. Pulmonary circulation. 2022. PMID: 35514780
- Xu Z, Zhang H, Zhang C. Association between Genotype, Presentation, and Outcome in Childhood Idiopathic and Hereditary Pulmonary Arterial Hypertension. Journal of clinical medicine. 2022. PMID: 36555947