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Primary pulmonary hypertension(PPH1)

MedGen UID:
57749
Concept ID:
C0152171
Disease or Syndrome
Synonyms: Heritable Pulmonary Arterial Hypertension; PPH1; Pulmonary arterial hypertension; PULMONARY HYPERTENSION, PRIMARY, 1
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Sources: HPO, OMIM, Orphanet
Autosomal dominant inheritance refers to genetic conditions that occur when a mutation is present in one copy of a given gene (i.e., the person is heterozygous).
not inherited
MedGen UID:
832438
Concept ID:
CN227390
Intellectual Product
Source: Orphanet
Describes a disorder that is not inherited.
Autosomal dominant inheritance (HPO, OMIM, Orphanet)
not inherited (Orphanet)
 
Gene (location): BMPR2 (2q33.1-33.2)
Related genes: SMAD9, KCNK3, CAV1
OMIM®: 178600
Orphanet: ORPHA182090

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 13q12; 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 2p24. 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).  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

Hypertension
MedGen UID:
6969
Concept ID:
C0020538
Disease or Syndrome
Blood pressure is the force of your blood pushing against the walls of your arteries. Each time your heart beats, it pumps blood into the arteries. Your blood pressure is highest when your heart beats, pumping the blood. This is called systolic pressure. When your heart is at rest, between beats, your blood pressure falls. This is called diastolic pressure. . Your blood pressure reading uses these two numbers. Usually the systolic number comes before or above the diastolic number. A reading of. -119/79 or lower is normal blood pressure. -140/90 or higher is high blood pressure. -Between 120 and 139 for the top number, or between 80 and 89 for the bottom number is called prehypertension. Prehypertension means you may end up with high blood pressure, unless you take steps to prevent it. High blood pressure usually has no symptoms, but it can cause serious problems such as stroke, heart failure, heart attack and kidney failure. You can control high blood pressure through healthy lifestyle habits such as exercise and the DASH diet and taking medicines, if needed. . NIH: National Heart, Lung, and Blood Institute.
Increased pulmonary vascular resistance
MedGen UID:
356775
Concept ID:
C1867423
Finding
Pulmonary arterial hypertension
MedGen UID:
468368
Concept ID:
C3203102
Disease or Syndrome
Pulmonary hypertension is defined mean pulmonary artery pressure of 25mmHg or more and pulmonary capillary wedge pressure of 15mmHg or less when measured by right heart catheterisation at rest and in a supine position.
Arterial intimal fibrosis
MedGen UID:
866496
Concept ID:
C4020753
Disease or Syndrome
Formation of excess fibrous connective tissue in the tunica intima (innermost layer) of arteries.
Dyspnea
MedGen UID:
3938
Concept ID:
C0013404
Sign or Symptom
Difficult or labored breathing.
Increased pulmonary vascular resistance
MedGen UID:
356775
Concept ID:
C1867423
Finding
Pulmonary arterial hypertension
MedGen UID:
468368
Concept ID:
C3203102
Disease or Syndrome
Pulmonary hypertension is defined mean pulmonary artery pressure of 25mmHg or more and pulmonary capillary wedge pressure of 15mmHg or less when measured by right heart catheterisation at rest and in a supine position.

Recent clinical studies

Etiology

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
Doepp F, Bähr D, John M, Hoernig S, Valdueza JM, Schreiber SJ
J Clin Ultrasound 2008 Oct;36(8):480-4. doi: 10.1002/jcu.20470. PMID: 18335510
Radulescu D, Pripon S, Duncea C, Constantea NA, Gulei I
Acta Med Indones 2008 Jan;40(1):24-8. PMID: 18326896
Carro-Jiménez EJ, López JE
Bol Asoc Med P R 2005 Oct-Dec;97(4):328-33. PMID: 16599074
Newman JH, Wheeler L, Lane KB, Loyd E, Gaddipati R, Phillips JA 3rd, Loyd JE
N Engl J Med 2001 Aug 2;345(5):319-24. doi: 10.1056/NEJM200108023450502. PMID: 11484688

Diagnosis

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
Sifuentes Giraldo WA, Ahijón Lana M, Gallego Rivera I, Bachiller Corral FJ, Gámir Gámir ML
Reumatol Clin 2012 Jul-Aug;8(4):208-11. Epub 2012 Jan 28 doi: 10.1016/j.reuma.2011.10.008. PMID: 22285205
Reutter H, Bagci S, Müller A, Gembruch U, Geipel A, Berg C, Eggermann T, Spengler S, Bartmann P, Rudnik-Schöneborn S
Eur J Med Genet 2012 Jan;55(1):27-31. Epub 2011 Oct 11 doi: 10.1016/j.ejmg.2011.09.002. PMID: 22044576
Radulescu D, Pripon S, Duncea C, Constantea NA, Gulei I
Acta Med Indones 2008 Jan;40(1):24-8. PMID: 18326896
Carro-Jiménez EJ, López JE
Bol Asoc Med P R 2005 Oct-Dec;97(4):328-33. PMID: 16599074

Therapy

Sifuentes Giraldo WA, Ahijón Lana M, Gallego Rivera I, Bachiller Corral FJ, Gámir Gámir ML
Reumatol Clin 2012 Jul-Aug;8(4):208-11. Epub 2012 Jan 28 doi: 10.1016/j.reuma.2011.10.008. PMID: 22285205
Senthil S, Kaur B, Jalali S, Garudadri C
Ophthalmic Surg Lasers Imaging 2009 Jan-Feb;40(1):50-3. PMID: 19205497
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
Sayin T, Ozenci M
Acta Cardiol 2007 Feb;62(1):47-9. doi: 10.2143/AC.62.1.2019370. PMID: 17375892
Chuesakoolvanich K, Boonsawat W, Mootsikapun P, Kiatchousakun S
J Med Assoc Thai 2005 Jul;88(7):979-83. PMID: 16241029

Prognosis

Amaki M, Nakatani S, Kanzaki H, Kyotani S, Nakanishi N, Shigemasa C, Hisatome I, Kitakaze M
Hypertens Res 2009 May;32(5):419-22. Epub 2009 Mar 27 doi: 10.1038/hr.2009.20. PMID: 19325565
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
De Castro S, Cavarretta E, Milan A, Caselli S, Di Angelantonio E, Vizza Carmine D, Lucchetti D, Patel A, Kuvin J, Pandian NG
Echocardiography 2008 Mar;25(3):289-93. doi: 10.1111/j.1540-8175.2007.00587.x. PMID: 18307442
Sayin T, Ozenci M
Acta Cardiol 2007 Feb;62(1):47-9. doi: 10.2143/AC.62.1.2019370. PMID: 17375892
Carro-Jiménez EJ, López JE
Bol Asoc Med P R 2005 Oct-Dec;97(4):328-33. PMID: 16599074

Clinical prediction guides

De Castro S, Cavarretta E, Milan A, Caselli S, Di Angelantonio E, Vizza Carmine D, Lucchetti D, Patel A, Kuvin J, Pandian NG
Echocardiography 2008 Mar;25(3):289-93. doi: 10.1111/j.1540-8175.2007.00587.x. PMID: 18307442
Zafrir N, Zingerman B, Solodky A, Ben-Dayan D, Sagie A, Sulkes J, Mats I, Kramer MR
Int J Cardiovasc Imaging 2007 Apr;23(2):209-15. Epub 2006 Sep 14 doi: 10.1007/s10554-006-9140-5. PMID: 16972146
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
McLaughlin VV, Sitbon O, Badesch DB, Barst RJ, Black C, Galiè N, Rainisio M, Simonneau G, Rubin LJ
Eur Respir J 2005 Feb;25(2):244-9. doi: 10.1183/09031936.05.00054804. PMID: 15684287
Krohn J, Bjune C
Am J Ophthalmol 2003 May;135(5):705-6. PMID: 12719080

Recent systematic reviews

Pass SE, Dusing ML
Ann Pharmacother 2002 Sep;36(9):1414-23. doi: 10.1345/aph.1C015. PMID: 12196062
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
Fauzi AR
Med J Malaysia 2000 Dec;55(4):529-37; quiz 538. PMID: 11221172
Herner SJ, Mauro LS
Ann Pharmacother 1999 Mar;33(3):340-7. doi: 10.1345/aph.17339. PMID: 10200860
McCann UD, Seiden LS, Rubin LJ, Ricaurte GA
JAMA 1997 Aug 27;278(8):666-72. PMID: 9272900

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