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Primary pulmonary hypertension(PPH1)

MedGen UID:
1643124
Concept ID:
C4552070
Disease or Syndrome
Synonyms: Heritable Pulmonary Arterial Hypertension; PPH1; PULMONARY HYPERTENSION, PRIMARY, 1
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Sources: HPO, OMIM, Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
Autosomal dominant inheritance (HPO, OMIM, Orphanet)
 
Gene (location): BMPR2 (2q33.1-33.2)
Related genes: SMAD9, KCNK3, CAV1
OMIM®: 178600

Disease characteristics

Excerpted from the GeneReview: Heritable Pulmonary Arterial Hypertension
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. [from GeneReviews]
Authors:
Eric D Austin  |  James E Loyd  |  John A Phillips   view full author information

Additional descriptions

From OMIM
Primary pulmonary arterial hypertension is a rare, often fatal, progressive vascular lung disease characterized by increased pulmonary vascular resistance and sustained elevation of mean pulmonary arterial pressure, leading to right ventricular hypertrophy and right heart failure. Pathologic features include a narrowing and thickening of small pulmonary vessels and plexiform lesions. There is pulmonary vascular remodeling of all layers of pulmonary arterial vessels: intimal thickening, smooth muscle cell hypertrophy or hyperplasia, adventitial fibrosis, and occluded vessels by in situ thrombosis (summary by Machado et al., 2009 and Han et al., 2013). Heterozygous mutations in the BMPR2 gene are found in nearly 70% of families with heritable PPH and in 25% of patients with sporadic disease. The disease is more common in women (female:male ratio of 1.7:1). However, the penetrance of PPH1 is incomplete: only about 10 to 20% of individuals with BMPR2 mutations develop the disease during their lifetime, suggesting that development of the disorder is triggered by other genetic or environmental factors. Patients with PPH1 are less likely to respond to acute vasodilater testing and are unlikely to benefit from treatment with calcium channel blockade (summary by Machado et al., 2009 and Han et al., 2013). Genetic Heterogeneity of Primary Pulmonary Hypertension PPH2 (615342) is caused by mutation in the SMAD9 gene (603295) on chromosome 13q13; PPH3 (615343) is caused by mutation in the CAV1 gene (601047) on chromosome 7q31; and PPH4 (615344) is caused by mutation in the KCNK3 gene (603220) on chromosome 2p23. See 265400 for a possible autosomal recessive form of PPH. Primary pulmonary hypertension may also be found in association with hereditary hemorrhagic telangiectasia type 1 (HHT1; 187300), caused by mutation in the ENG gene (131195), and HHT2 (600376), caused by mutation in the ACVRL1 (ALK1) gene (601284). Pediatric-onset pulmonary hypertension may be seen in association with ischiocoxopodopatellar syndrome (ICPPS; 147891). The skeletal manifestations of ICPPS are highly variable and may not be detected in children. Parents are not likely to have PAH (Levy et al., 2016).  http://www.omim.org/entry/178600
From GHR
Pulmonary arterial hypertension is a progressive disorder characterized by abnormally high blood pressure (hypertension) in the pulmonary artery, the blood vessel that carries blood from the heart to the lungs. Pulmonary arterial hypertension is one form of a broader condition known as pulmonary hypertension. Pulmonary hypertension occurs when most of the very small arteries throughout the lungs narrow in diameter, which increases the resistance to blood flow through the lungs. To overcome the increased resistance, blood pressure increases in the pulmonary artery and in the right ventricle of the heart, which is the chamber that pumps blood into the pulmonary artery. Ultimately, the increased blood pressure can damage the right ventricle of the heart.Signs and symptoms of pulmonary arterial hypertension occur when increased blood pressure cannot fully overcome the elevated resistance. As a result, the flow of oxygenated blood from the lungs to the rest of the body is insufficient. Shortness of breath (dyspnea) during exertion and fainting spells are the most common symptoms of pulmonary arterial hypertension. People with this disorder may experience additional symptoms, particularly as the condition worsens. Other symptoms include dizziness, swelling (edema) of the ankles or legs, chest pain, and a rapid heart rate.  https://ghr.nlm.nih.gov/condition/pulmonary-arterial-hypertension

Clinical features

From HPO
Hypertension
MedGen UID:
6969
Concept ID:
C0020538
Disease or Syndrome
Blood pressure that is abnormally high.
Telangiectasia
MedGen UID:
21088
Concept ID:
C0039446
Finding
Local dilatation of small vessels resulting in red discoloration of the skin or mucous membranes.
Right ventricular hypertrophy
MedGen UID:
57981
Concept ID:
C0162770
Disease or Syndrome
Enlargement of the RIGHT VENTRICLE of the heart. This increase in ventricular mass is often attributed to PULMONARY HYPERTENSION and is a contributor to cardiovascular morbidity and mortality.
Pulmonary arterial medial hypertrophy
MedGen UID:
306155
Concept ID:
C1504382
Disease or Syndrome
Increase in mass of the tunica media of the arteries in the pulmonary circulation.
Elevated right atrial pressure
MedGen UID:
357982
Concept ID:
C1867421
Finding
An abnormal increase in magnitude of the pressure in the right atrium.
Increased pulmonary vascular resistance
MedGen UID:
356775
Concept ID:
C1867423
Finding
Pulmonary artery vasoconstriction
MedGen UID:
357276
Concept ID:
C1867424
Finding
Right ventricular failure
MedGen UID:
424852
Concept ID:
C2939447
Disease or Syndrome
Failure of proper functioning of the right ventricle, with venous engorgement, hepatic enlargement, and subcutaneous edema.
Pulmonary arterial hypertension
MedGen UID:
425404
Concept ID:
C2973725
Disease or Syndrome
A progressive rare pulmonary disease characterized by high blood pressure in the PULMONARY ARTERY.
Arterial intimal fibrosis
MedGen UID:
893098
Concept ID:
C4023403
Disease or Syndrome
Formation of excess fibrous connective tissue in the tunica intima (innermost layer) of arteries.
Pulmonary aterial intimal fibrosis
MedGen UID:
870760
Concept ID:
C4025217
Disease or Syndrome
Formation of excess fibrous connective tissue in the tunica intima (innermost layer) of arteries in the pulmonary circulation.
Abnormal thrombosis
MedGen UID:
871247
Concept ID:
C4025731
Anatomical Abnormality
Venous or arterial thrombosis (formation of blood clots) of spontaneous nature and which cannot be fully explained by acquired risk (e.g. atherosclerosis).
Dyspnea
MedGen UID:
3938
Concept ID:
C0013404
Sign or Symptom
Difficult or labored breathing.
Pulmonary arterial medial hypertrophy
MedGen UID:
306155
Concept ID:
C1504382
Disease or Syndrome
Increase in mass of the tunica media of the arteries in the pulmonary circulation.
Increased pulmonary vascular resistance
MedGen UID:
356775
Concept ID:
C1867423
Finding
Pulmonary artery vasoconstriction
MedGen UID:
357276
Concept ID:
C1867424
Finding
Pulmonary arterial hypertension
MedGen UID:
425404
Concept ID:
C2973725
Disease or Syndrome
A progressive rare pulmonary disease characterized by high blood pressure in the PULMONARY ARTERY.
Pulmonary aterial intimal fibrosis
MedGen UID:
870760
Concept ID:
C4025217
Disease or Syndrome
Formation of excess fibrous connective tissue in the tunica intima (innermost layer) of arteries in the pulmonary circulation.
Telangiectasia
MedGen UID:
21088
Concept ID:
C0039446
Finding
Local dilatation of small vessels resulting in red discoloration of the skin or mucous membranes.

Term Hierarchy

Recent clinical studies

Etiology

de-Miguel-Díez J, Lopez-de-Andres A, Hernandez-Barrera V, Jimenez-Trujillo I, Mendez-Bailon M, de Miguel-Yanes JM, Muñoz-Rivas N, Romero-Maroto M, Jimenez-Garcia R
Medicine (Baltimore) 2019 May;98(18):e15518. doi: 10.1097/MD.0000000000015518. PMID: 31045844Free PMC Article
Andijani AA, Shajira ES, Abushaheen A, Al-Matary A
Am J Case Rep 2019 Mar 18;20:354-360. doi: 10.12659/AJCR.912873. PMID: 30880327Free PMC Article
Sajjad A, Weng CY
Retin Cases Brief Rep 2017 Fall;11(4):325-328. doi: 10.1097/ICB.0000000000000355. PMID: 27355186
Mazimba S, Mejia-Lopez E, Black G, Kennedy JL, Bergin J, Tallaj JA, Abuannadi M, Mihalek AD, Bilchick KC
Respir Med 2016 Oct;119:81-86. Epub 2016 Aug 25 doi: 10.1016/j.rmed.2016.08.024. PMID: 27692153
Chakravarty EF, Khanna D, Chung L
Obstet Gynecol 2008 Apr;111(4):927-34. doi: 10.1097/01.AOG.0000308710.86880.a6. PMID: 18378753Free PMC Article

Diagnosis

Chioukh FZ, Monastiri K
J Coll Physicians Surg Pak 2019 Jun;29(6):S43-S44. doi: 10.29271/jcpsp.2019.06.S43. PMID: 31142418
Feng Z, Dong L, Cao J, Bai J, Yang MM, Zheng Y, Lin D
Int Ophthalmol 2018 Feb;38(1):375-379. Epub 2017 Jan 21 doi: 10.1007/s10792-017-0443-4. PMID: 28108900
Mazimba S, Mejia-Lopez E, Black G, Kennedy JL, Bergin J, Tallaj JA, Abuannadi M, Mihalek AD, Bilchick KC
Respir Med 2016 Oct;119:81-86. Epub 2016 Aug 25 doi: 10.1016/j.rmed.2016.08.024. PMID: 27692153
Sharma AK, Nath RK, Pandit N
Hellenic J Cardiol 2016 Mar-Apr;57(2):124-8. Epub 2016 Apr 5 doi: 10.1016/j.hjc.2016.03.005. PMID: 27445029
Shankar O, Lohiya BV
Indian Heart J 2014 May-Jun;66(3):375-7. Epub 2014 Apr 21 doi: 10.1016/j.ihj.2013.12.055. PMID: 24973850Free PMC Article

Therapy

Chioukh FZ, Monastiri K
J Coll Physicians Surg Pak 2019 Jun;29(6):S43-S44. doi: 10.29271/jcpsp.2019.06.S43. PMID: 31142418
Ben Bouallègue F, Vauchot F, Bourdon A, Benkiran M, Boissin C, Charriot J, Bourdin A, Mariano-Goulart D
J Nucl Cardiol 2018 Dec;25(6):2174-2176. Epub 2018 Jan 10 doi: 10.1007/s12350-017-1171-x. PMID: 29322380
Wu J, Jia J, Liu L, Yang F, Fan Y, Zhang S, Yan D, Bu R, Li G, Gao Y, Chen Y
J Am Soc Hypertens 2017 Mar;11(3):148-157.e1. Epub 2016 Dec 28 doi: 10.1016/j.jash.2016.12.007. PMID: 28117274
Sajjad A, Weng CY
Retin Cases Brief Rep 2017 Fall;11(4):325-328. doi: 10.1097/ICB.0000000000000355. PMID: 27355186
Mazimba S, Mejia-Lopez E, Black G, Kennedy JL, Bergin J, Tallaj JA, Abuannadi M, Mihalek AD, Bilchick KC
Respir Med 2016 Oct;119:81-86. Epub 2016 Aug 25 doi: 10.1016/j.rmed.2016.08.024. PMID: 27692153

Prognosis

Chioukh FZ, Monastiri K
J Coll Physicians Surg Pak 2019 Jun;29(6):S43-S44. doi: 10.29271/jcpsp.2019.06.S43. PMID: 31142418
de-Miguel-Díez J, Lopez-de-Andres A, Hernandez-Barrera V, Jimenez-Trujillo I, Mendez-Bailon M, de Miguel-Yanes JM, Muñoz-Rivas N, Romero-Maroto M, Jimenez-Garcia R
Medicine (Baltimore) 2019 May;98(18):e15518. doi: 10.1097/MD.0000000000015518. PMID: 31045844Free PMC Article
Andijani AA, Shajira ES, Abushaheen A, Al-Matary A
Am J Case Rep 2019 Mar 18;20:354-360. doi: 10.12659/AJCR.912873. PMID: 30880327Free PMC Article
Mazimba S, Mejia-Lopez E, Black G, Kennedy JL, Bergin J, Tallaj JA, Abuannadi M, Mihalek AD, Bilchick KC
Respir Med 2016 Oct;119:81-86. Epub 2016 Aug 25 doi: 10.1016/j.rmed.2016.08.024. PMID: 27692153
Toyama H, Wagatsuma T, Ejima Y, Matsubara M, Kurosawa S
Int J Obstet Anesth 2009 Jul;18(3):262-7. Epub 2009 Jan 20 doi: 10.1016/j.ijoa.2008.08.001. PMID: 19157850

Clinical prediction guides

de-Miguel-Díez J, Lopez-de-Andres A, Hernandez-Barrera V, Jimenez-Trujillo I, Mendez-Bailon M, de Miguel-Yanes JM, Muñoz-Rivas N, Romero-Maroto M, Jimenez-Garcia R
Medicine (Baltimore) 2019 May;98(18):e15518. doi: 10.1097/MD.0000000000015518. PMID: 31045844Free PMC Article
Wu J, Jia J, Liu L, Yang F, Fan Y, Zhang S, Yan D, Bu R, Li G, Gao Y, Chen Y
J Am Soc Hypertens 2017 Mar;11(3):148-157.e1. Epub 2016 Dec 28 doi: 10.1016/j.jash.2016.12.007. PMID: 28117274
Sajjad A, Weng CY
Retin Cases Brief Rep 2017 Fall;11(4):325-328. doi: 10.1097/ICB.0000000000000355. PMID: 27355186
Mazimba S, Mejia-Lopez E, Black G, Kennedy JL, Bergin J, Tallaj JA, Abuannadi M, Mihalek AD, Bilchick KC
Respir Med 2016 Oct;119:81-86. Epub 2016 Aug 25 doi: 10.1016/j.rmed.2016.08.024. PMID: 27692153
Remy-Jardin M, Duhamel A, Deken V, Bouaziz N, Dumont P, Remy J
Radiology 2005 Apr;235(1):274-81. Epub 2005 Feb 9 doi: 10.1148/radiol.2351040335. PMID: 15703314

Recent systematic reviews

Dathe K, Hultzsch S, Pritchard LW, Schaefer C
Eur J Clin Pharmacol 2019 Oct;75(10):1347-1353. Epub 2019 Jul 4 doi: 10.1007/s00228-019-02712-2. PMID: 31273431
Kuang HY, Wu YH, Yi QJ, Tian J, Wu C, Shou WN, Lu TW
Medicine (Baltimore) 2018 Mar;97(10):e0075. doi: 10.1097/MD.0000000000010075. PMID: 29517668Free PMC Article
Paramothayan NS, Lasserson TJ, Wells AU, Walters EH
Cochrane Database Syst Rev 2003;(2):CD002994. doi: 10.1002/14651858.CD002994. PMID: 12804447
Pellicelli AM, Barbaro G, Palmieri F, Girardi E, D'Ambrosio C, Rianda A, Barbarini G, Frigiotti D, Borgia MC, Petrosillo N
Angiology 2001 Jan;52(1):31-41. doi: 10.1177/000331970105200105. PMID: 11205929
McCann UD, Seiden LS, Rubin LJ, Ricaurte GA
JAMA 1997 Aug 27;278(8):666-72. PMID: 9272900

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