Alternative titles; symbols
Other entities represented in this entry:
SNOMEDCT: 697898008; ICD10CM: I27.0; ORPHA: 275777, 422; DO: 14557;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2q33.1-q33.2 | Pulmonary hypertension, primary, fenfluramine or dexfenfluramine-associated | 178600 | Autosomal dominant | 3 | BMPR2 | 600799 |
| 2q33.1-q33.2 | Pulmonary hypertension, familial primary, 1, with or without HHT | 178600 | Autosomal dominant | 3 | BMPR2 | 600799 |
A number sign (#) is used with this entry because of evidence that primary pulmonary hypertension-1 (PPH1) is caused by heterozygous mutation in the BMPR2 gene (600799) on chromosome 2q33.
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
See also PPH2 (615342), caused by mutation in the SMAD9 gene (603295) on chromosome 13q13; PPH3 (615343), caused by mutation in the CAV1 gene (601047) on chromosome 7q31; PPH4 (615344), caused by mutation in the KCNK3 gene (603220) on chromosome 2p23; PPH5 (265400), caused by mutation in the ATP13A3 gene (610232) on chromosome 3q29; and PPH6 (620777), caused by mutation in the CAPNS1 gene (114170) on chromosome 19q13.
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).
Melmon and Braunwald (1963) observed 2 proved cases and 3 presumptive cases of primary pulmonary hypertension (PPH) in 3 generations of a family. Parry and Verel (1966) described the disorder in a mother and her 2 daughters and referred to at least 2 other reports of 2 generations being affected. Kingdon et al. (1966) described the condition in brother and sister and their father.
Morse et al. (1992) described a kindred in which 7 members had primary pulmonary hypertension and 2 others had this probable diagnosis. The proband was an 11-year-old girl who had an affected 8-year-old sister. The paternal grandmother died at the age of 21 in severe right heart failure, 3 days after delivering her third child. Three other remarkable families were reported. In affected members of a family with pulmonary hypertension, Inglesby et al. (1973) found elevated levels of antiplasmin (613168).
Pulmonary Hypertension with Hereditary Hemorrhagic Telangiectasia
Rigelsky et al. (2008) reported a woman diagnosed with pulmonary hypertension at age 24 years. She developed massive hemoptysis at age 35, prompting the discovery of multiple pulmonary arteriovenous malformations consistent with a diagnosis of hereditary hemorrhagic telangiectasia. She also had recurrent epistaxis and nasal telangiectasia. The patient was adopted, and there was no family history available. Genetic analysis revealed a heterozygous mutation in the BMPR2 gene (Q433X; 600799.0026). Mutations in the ACVRL1, ENG (131195), and SMAD4 (600993) genes were excluded. Rigelsky et al. (2008) noted that, although PAH with HHT had usually only been associated with mutations in the ACVRL1 gene, their patient was the first report of PAH and HHT associated with a mutation in the BMPR2 gene. The findings indicated a common molecular pathogenesis in PAH and HHT, most likely dysregulated BMP9 (GDF2; 605120) signaling.
Gaine and Rubin (1998) reviewed progress in treatment of PPH. The prognosis of untreated PPH is poor. Treatment with oral calcium channel blockers is helpful for a very small percentage of PPH patients, and oral anticoagulation therapy was standard care at the time of the report. Treatment with continuous intravenous epoprostenol had been shown in randomized trials to prolong life and improve clinical function, but it is complicated (requires a chronic indwelling central venous catheter) and expensive. Lung transplantation is a final alternative therapy for patients who do not improve with medical therapies.
Familial PPH is rare and has an incidence of approximately 1 in 100,000 to 1 in 1,000,000. Familial PPH has an autosomal dominant mode of inheritance, reduced penetrance, affects more females than males, and exhibits genetic anticipation (Deng et al., 2000; the International PPH Consortium et al., 2000). Quoting Rich et al. (1987), Rubin (1997) stated that 'familial primary pulmonary hypertension accounted for 6 percent of the 187 cases in the NIH registry.' Incomplete penetrance and a 2-5:1 female predilection is evident in the analysis of published cases. X-linked inheritance is excluded by rare instances of male-to-male transmission and, in one case, of transmission from grandfather to grandson through an unaffected son (Newman, 1981).
Loyd et al. (1984) presented compelling evidence of autosomal dominant inheritance with female preference. They observed 6 deaths from PPH in 2 generations: 4 sisters and 1 daughter of each of 2 of the sisters. In a survey of 9 of the 13 families with PPH reported from North America, they found 8 new cases of PPH in 5 of the 9. There was a 2 to 1 female-to-male ratio, but in one instance male-to-male transmission was observed. In one family, the gene was apparently transmitted from an affected male through 2 generations of unaffected females to a male who died of the disease at age 6.
Loyd et al. (1995) found a pattern of autosomal dominant inheritance with anticipation, a worsening of the disease in successive generations.
Morse et al. (1997) used linkage analysis to map the PPH1 gene to chromosome 2q31-q32 in 2 ethnically distinct families.
Following a genomewide search using a set of highly polymorphic short tandem repeat (STR) markers and 19 affected individuals from 6 families, Nichols et al. (1997) obtained initial evidence for linkage with 2 chromosome 2q markers. They subsequently genotyped patients and all available family members for 19 additional markers spanning approximately 40 cM on the long arm of chromosome 2. In this way they obtained a maximum 2-point lod score of 6.97 at theta = 0.0 with marker D2S389. Multipoint linkage analysis yielded a maximum lod score of 7.86 with the marker D2S311. Haplotype analysis established a minimum candidate interval of approximately 25 cM.
Heterogeneity
Morse et al. (1992) suggested that a familial form of primary pulmonary hypertension may have a susceptibility factor located within or near the MHC locus on chromosome 6p.
Members of the TGF-beta superfamily (see, e.g. 190180), including TGFB, BMPs, and activin, transduce signals by binding to heteromeric complexes of type I and II serine/threonine kinase receptors, leading to transcriptional regulation by phosphorylated Smads (e.g., 601366). The BMPR2 and ACVRL1 genes encode type II and type I serine/threonine kinase receptors, respectively. Mutation in the SMAD9 gene (also known as SMAD8) suggests that downregulation of the downstream TGFB/BMP signaling pathway may play a role in primary pulmonary hypertension (International PPH Consortium et al., 2000; Shintani et al., 2009).
The International PPH Consortium et al. (2000) and Deng et al. (2000) showed that PPH1 is caused by mutations in the BMPR2 gene (600799). These BMPR2 mutations were found in 7 of 8 families exhibiting linkage to markers adjacent to BMPR2 by the International PPH Consortium et al. (2000) and in 9 of 19 of the families exhibiting linkage and/or haplotype sharing with markers adjacent to BMPR2 by Deng et al. (2000). Both groups found that the BMPR2 mutations are heterogeneous and include termination, frameshift, and nonconservative missense changes in amino acid sequence. By comparison with in vitro studies, the International PPH Consortium et al. (2000) predicted that the identified BMPR2 mutations would disrupt ligand binding, kinase activity, and heteromeric dimer formation.
Eddahibi et al. (2001) reported that pulmonary artery smooth muscle cells (SMCs) from patients with PPH grew faster than those from controls when stimulated with serum or serotonin, due to increased expression of 5-HTT (182138). Inhibitors of 5-HTT attenuated the growth-stimulatory effects of serum and serotonin. Expression of 5-HTT was increased in cultured pulmonary artery SMCs as well as in platelets and lungs from patients with PPH, where it predominated in the media of thickened pulmonary arteries and in onion bulb lesions. The L allele variant of the 5-HTT promoter (182138.0001), which is associated with 5-HTT overexpression and increased pulmonary artery SMC growth, was present in homozygous form in 65% of PPH patients but in only 27% of controls (p less than 0.001). Eddahibi et al. (2001) concluded that 5-HTT activity plays a key role in the pathogenesis of pulmonary artery SMC proliferation in PPH and that a 5-HTT polymorphism confers susceptibility to PPH.
Thomson et al. (2000) analyzed the BMPR2 gene in 50 unrelated patients with sporadic PPH and identified 11 different heterozygous mutations in 13 of the 50 PPH patients, including 3 missense, 3 nonsense (see, e.g., 600799.0019), and 5 frameshift mutations. Analysis of parental DNA was possible in 5 cases and showed 3 occurrences of paternal transmission and 2 of de novo mutation of the BMPR2 gene. Thomson et al. (2000) noted that because of low penetrance, in the absence of detailed genealogic data, familial cases may be overlooked.
Humbert et al. (2002) analyzed the BMPR2 gene in 33 unrelated patients with sporadic PPH and 2 sisters with PPH, all of whom had taken fenfluramine derivatives. Three BMPR2 mutations (see, e.g., 600799.0020) were identified in 3 (9%) of the 33 unrelated patients, and a fourth mutation (R211X; 600799.0019) was identified in the 2 sisters. Mutation-positive patients had similar clinical and hemodynamic characteristics when compared to mutation-negative patients, except for a shorter duration of exposure to fenfluramine derivatives before illness (median exposure, 1 month and 4 months, respectively). Humbert et al. (2002) concluded that BMPR2 mutations may combine with exposure to fenfluramine derivatives to greatly increase the risk of developing severe pulmonary arterial hypertension.
In 25 families with PPH and 106 patients with sporadic PPH, all of whom were negative for mutations in the BMPR2 gene by DHPLC analysis or direct sequencing, Aldred et al. (2006) performed multiplex ligation-dependent probe amplification (MLPA) analysis to detect gross BMPR2 rearrangements. Ten different deletions were identified in 7 families and 6 sporadic cases (see, e.g., 600799.0023-600799.0025). One patient with familial PPH had histologic features of pulmonary venoocclusive disease (PVOD; 265450) and was found to have a deletion of exon 2 of the BMPR2 gene (600799.0023); the exon 2 deletion was also identified in an unrelated family with PPH and no known evidence of PVOD. Aldred et al. (2006) noted that 2 large deletions were predicted to result in null alleles (see 600799.0025), providing support for the hypothesis that the predominant molecular mechanism for disease predisposition is haploinsufficiency.
Shintani et al. (2009) identified a heterozygous truncating mutation in the SMAD9 gene (603295.0001) in a patient with PPH. The mutant protein resulted in downregulation of the downstream TGFB/BMP signaling pathway.
Phillips et al. (2008) studied SNP genotypes of TGF-beta (190180) in BMPR2 mutation carriers with pulmonary hypertension and examined the age of diagnosis and penetrance of the pulmonary hypertension phenotype. BMPR2 heterozygotes with least active -509 or codon 10 TGFB1 SNPs had later mean age at diagnosis of familial pulmonary arterial hypertension (39.5 and 43.2 years, respectively) than those with more active genotypes (31.6 and 33.1 years, P = 0.03 and 0.02, respectively). Kaplan-Meier analysis showed that those with less active SNPs had later age at diagnosis. BMPR2 mutation heterozygotes with nonsense-mediated decay-resistant BMPR2 mutations and the least, intermediate, and most active -509 TGFB1 SNP phenotypes had penetrances of 33%, 72%, and 80%, respectively (P = 0.003), whereas those with 0-1, 2, or 3-4 active SNP alleles had penetrances of 33%, 72%, and 75% (P = 0.005). Phillips et al. (2008) concluded that the TGFB1 SNPs studied modulate age at diagnosis and penetrance of familial pulmonary arterial hypertension in BMPR2 mutation heterozygotes, likely by affecting TGFB/BMP signaling imbalance. The authors considered this modulation an example of synergistic heterozygosity.
Heterogeneity
Grunig et al. (2004) analyzed the BMPR2 gene in 13 unrelated children with PPH diagnosed between the ages of 6 months and 13 years and invasively confirmed, but found no mutations or deletions. Linkage to chromosomes 2 or 12 could not be confirmed in any of 6 families studied. Evaluation of 57 members of 6 families revealed that both parents of the index patient and/or members of both branches had an abnormal pulmonary artery systolic pressure response to exercise. Grunig et al. (2004) concluded that PPH in children may have a different genetic background than in adults, and postulated a recessive mode of inheritance in a proportion of infantile cases.
Associations Pending Confirmation
Germain et al. (2013) conducted a genomewide association study based on 2 independent case-control studies for idiopathic and familial PAH (without BMPR2 mutations), including a total of 625 cases and 1,525 healthy individuals. Germain et al. (2013) detected a significant association at the CBLN2 locus (600433) mapping to chromosome 18q22.3, with the risk allele conferring an odds ratio for PAH of 1.97 (1.59-2.45; p = 7.47 x 10(-10)). CBLN2 is expressed in the lung, and its expression was higher in explanted lungs from individuals with PAH and in endothelial cells cultured from explanted PAH lungs than in control samples.
In the Finnish population, Sankelo et al. (2005) reported that prevalence of PPH was 5.8 cases per million and annual incidence was 0.2 to 1.3 cases per million. Detailed molecular analysis of 26 sporadic patients and 4 familial cases failed to identify a common founder BMPR2 mutation in this genetically homogeneous population, suggesting that pathogenic BMPR2 mutations are relatively young.
Recurrent pulmonary microembolization with impaired fibrinolysis had been postulated but not proved as the basis of this disorder. Herve et al. (1990) suggested that inherited platelet storage deficiency with a high level of 5-hydroxytryptamine in plasma can be a cause of 'primary' pulmonary hypertension. In 3 Caucasian kindreds with familial primary pulmonary hypertension, Morse et al. (1992) found that each family had 1 affected person with an IgA or IgG immunoglobulin deficiency and a specific HLA (142800) typing (HLA-DR3, DRw52,DQw2). Some affected members of a fourth family had autoantibodies and different HLA associations. The authors suggested a susceptibility factor within or near the MHC locus.
Plexiform lesions composed of proliferating endothelial cells occur in 20 to 80% of cases of primary pulmonary hypertension. Lee et al. (1998) studied the question of whether the endothelial cell proliferation in these lesions in PPH is monoclonal or polyclonal by means of the methylation pattern of the androgen receptor gene (313700) by PCR, in proliferating endothelial cells in plexiform lesions from female 4 PPH patients compared with 4 secondary pulmonary hypertension patients. In PPH, 17 of 22 lesions (77%) were monoclonal; however, in secondary PH, all 19 lesions examined were polyclonal. Smooth muscle cell hyperplasia in 11 pulmonary vessels in PPH and secondary PH was polyclonal in all but 1 of the examined vessels. The findings of frequent monoclonal endothelial cell proliferation in PPH suggested that a somatic genetic alteration similar to that present in neoplastic processes may be responsible for the pathogenesis of PPH.
Loyd et al. (1988) analyzed the findings in lung specimens from 23 affected members from 13 families. They found marked heterogeneity in the pathologic lesions within and among families, including frequent coexistence of thrombotic and plexiform lesions. They concluded that the proposed existence of 2 pathologic types of primary pulmonary hypertension, plexogenic and thromboembolic, is probably not valid. They noted that the lesions found in this disorder are not specific but represent different manifestations of the same pathologic process.
Loscalzo (2001) noted that a subset of patients with hereditary hemorrhagic telangiectasia have lung disease that is similar to PPH. The pathologic features of the blood vessels of these patients consist of vascular dilatations and arteriovenous fistulas characteristic of HHT (see 600376), as well as the occlusive arteriopathy of PPH. Loscalzo (2001) presented a hypothetical model of the role of mutations in the BMPR2 and ALK1 (ACVRL1; 601284) genes in the development of primary pulmonary hypertension and PPH with hereditary hemorrhagic telangiectasia, respectively.
The spectrum of trigger factors and molecular mechanisms leading to severe pulmonary hypertension and the formation of plexiform lesions is wide, including both genetic and epigenetic factors. Cool et al. (2003) suggested that infection with the vasculotropic virus HHV-8, the etiologic agent of Kaposi sarcoma (148000), may have a pathogenetic role in primary pulmonary hypertension.
Machado et al. (2003) determined that TCTEL1 (601544), a light chain of the motor complex dynein, interacted with the cytoplasmic domain of BMPR2 and was also phosphorylated by BMPR2, a function disrupted by PPH1-causing mutations within exon 12 (e.g., 600799.0002). BMPR2 and TCTEL1 colocalized to endothelium and smooth muscle within the media of pulmonary arterioles, key sites of vascular remodeling in PPH. The authors proposed that loss of interaction and lack of phosphorylation of TCTEL1 by BMPR2 may contribute to the pathogenesis of PPH.
Li et al. (2009) demonstrated that PAH is characterized by overexpression of NOTCH3 (600276) in small pulmonary artery smooth muscle cells (SMCs) and that the severity of disease in humans and rodents correlates with the amount of NOTCH3 protein in the lung. Notch3 -/- mice did not develop pulmonary hypertension in response to hypoxic stimulation, and both pulmonary hypertension and right ventricular hypertrophy were ameliorated in mice by treatment with DAPT, a gamma-secretase (see 104311) inhibitor that blocks activation of NOTCH3 in SMCs. The authors demonstrated a mechanistic link from NOTCH3 receptor signaling through the HES5 protein (607348) to SMC proliferation and a shift to an undifferentiated SMC phenotype. Li et al. (2009) suggested that the NOTCH3-HES5 signaling pathway is crucial for the development of PAH.
In pulmonary endothelial cells derived from 2 of 3 PPH1 patients with BMPR2 mutations, Drake et al. (2011) found loss of miR21 (611020) induction in response to BMP9 (605120). These cells also showed greater proliferation compared to controls; overexpression of miR21 induced growth suppression. However, canonical BMP signaling was only mildly attenuated in these cells. The findings suggested that disruption of the noncanonical BMP-mediated pathway resulting in aberrant miR processing may play an important role in the pathogenesis of PPH.
See 178400 for discussion of pulmonary hypertension in cattle at high altitude.
Noting that vasoactive intestinal peptide (VIP; 192320) had been reported absent in pulmonary arteries from patients with idiopathic pulmonary arterial hypertension, Said et al. (2007) generated Vip -/- mice and examined them for evidence of PAH. Vip -/- mice exhibited moderate right ventricular (RV) hypertension, RV hypertrophy confirmed by increased ratio of RV to left ventricle plus septum weight, and an enlarged, thickened pulmonary artery and smaller branches with increased muscularization and narrowed lumens compared to wildtype mice. Lung sections also showed perivascular inflammatory cell infiltrates. There was no systemic hypertension or arterial hypoxemia to explain the PAH. The condition was associated with increased mortality. Both the vascular remodeling and RV remodeling were attenuated after a 4-week treatment with VIP. Said et al. (2007) concluded that the Vip -/- mouse was not an exact model of PAH but would be useful for studying molecular mechanisms of PAH and evaluating potential therapeutic agents.
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