PPH1 WITH HHT, INCLUDED
PAH PULMONARY HYPERTENSION, PRIMARY, DEXFENFLURAMINE-ASSOCIATED, INCLUDED
PULMONARY HYPERTENSION, PRIMARY, 1, WITH HEREDITARY HEMORRHAGIC TELANGIECTASIA, INCLUDED
PULMONARY HYPERTENSION, PRIMARY, FENFLURAMINE-ASSOCIATED, INCLUDED
PULMONARY ARTERIAL HYPERTENSION
PHT
PPH1
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 ... 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).
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 ... 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.
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 ... 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.
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 ... 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.