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Rev Mal Respir ; 35(2): 160-170, 2018 Feb.
Article Fr | MEDLINE | ID: mdl-29501213

Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary hypertension (PH) characterized by preferential remodelling of pulmonary venules and angioproliferation. PVOD term includes idiopathic, heritable (biallelic mutations of EIF2AK4 gene), drugs and toxins induced (alkylating agents, organic solvents) and connectivite-associated forms (especially systemic-sclerosis associated form). PVOD and pulmonary arterial hypertension (PAH) share a similar clinical presentation. Lung biopsy is contraindicated in PVOD due to high risk of life-threatening bleeding. A noninvasive diagnostic approach, including oxygen parameters, low diffusing capacity for carbon monoxide and characteristic signs on high-resolution computed tomography of the chest, is used to support a diagnosis of PVOD. PVOD prognosis is worse than other forms of PAH. There is no evidence-based medical therapy for PVOD and life-threatening pulmonary edema may occur following PAH targeted therapy in PVOD. Lung transplantation remains the preferred definitive therapy for eligible patients.

Pulmonary Veno-Occlusive Disease , Animals , Diagnostic Imaging/methods , Disease Models, Animal , Humans , Pulmonary Veno-Occlusive Disease/diagnosis , Pulmonary Veno-Occlusive Disease/epidemiology , Pulmonary Veno-Occlusive Disease/therapy , Rare Diseases/diagnosis , Rare Diseases/epidemiology , Rare Diseases/therapy , Respiratory Function Tests/methods , Risk Factors
Rev Mal Respir ; 33(6): 460-73, 2016 Jun.
Article En | MEDLINE | ID: mdl-26868668

INTRODUCTION: Type 1 neurofibromatosis is one of the most common genetic diseases, with an incidence of 1/3500 live births. Its diagnosis primarily relies on the clinical features of the condition. CURRENT KNOWLEDGE: The life expectancy of these patients is reduced by 10 years, on average, compared to the general population. Type 1 neurofibromatosis has been shown to increase the risk of various types of neoplasia, primarily those affecting the neural crest. In addition, interstitial lung disease, lung cancer, and pulmonary hypertension have been observed during the third or the fourth decade of an adult's life. PERSPECTIVES: There are only few case reports available that address the pulmonary complications of neurofibromatosis type 1. It is thus crucial to fully understand this rare disease and its potential complications in order to allow for early diagnosis so we are able to improve the quality of life and survival of those suffering from the condition. CONCLUSIONS: The pulmonary complications of type 1 neurofibromatosis can be severe and life-threatening. Patients with this condition should thus undergo regular clinical visits and examinations to allow pulmonary complications to be detected and treatment to be initiated as early as possible.

Lung Diseases/etiology , Neurofibromatosis 1/complications , Humans , Hypertension, Pulmonary/diagnosis , Hypertension, Pulmonary/etiology , Lung Diseases/diagnosis , Lung Diseases, Interstitial/diagnosis , Lung Diseases, Interstitial/etiology , Lung Neoplasms/diagnosis , Lung Neoplasms/etiology , Neurofibromatosis 1/diagnosis , Neurofibromatosis 1/genetics , Rare Diseases
Clin Pharmacol Ther ; 95(6): 583-5, 2014 Jun.
Article En | MEDLINE | ID: mdl-24842639

Bosentan is an endothelin receptor antagonist used as a first-line treatment in pulmonary arterial hypertension (PAH). Its main adverse effect is a dose-dependent liver toxicity. CYP2C9*2 has recently been shown to be associated with hepatotoxicity in PAH patients. We conducted a nested case-control study to further explore the relationship between functional polymorphisms of gene products involved in bosentan pharmacokinetics (OATP1B1, OATP1B3, and CYP2C9) or hepatobiliary transporters affected by bosentan (ABCB11) and bosentan-induced liver toxicity.

Aryl Hydrocarbon Hydroxylases/genetics , Chemical and Drug Induced Liver Injury/etiology , Endothelin Receptor Antagonists , Hypertension, Pulmonary/drug therapy , Sulfonamides/adverse effects , Female , Humans , Male
Clin Genet ; 82(2): 173-9, 2012 Aug.
Article En | MEDLINE | ID: mdl-21651515

Germline mutations in genes encoding members of the transforming growth factor-ß (TGF-ß)/bone morphogenetic protein (BMP) superfamily are causal for two hereditary vascular disorders, hereditary hemorrhagic telangiectasia (HHT) and heritable pulmonary arterial hypertension (PAH). When the two diseases coexist, activin A receptor type II-like kinase-1 (ACVRL1) gene mutations are usually identified. We report a remarkable ACVRL1 germinal and somatic mosaicism characterized by the presence of two distinct mutant alleles and a non-mutant ACVRL1 allele in a woman diagnosed with PAH at the age 40. She also met the Curaçao diagnostic criteria for HHT based on additional findings of telangiectases, epistaxis and arteriovenous malformations. Mutation analysis of ACVRL1 identified two adjacent heterozygous deleterious mutations within exon 10: c.1388del (p.Gly463fsX2) and c.1390del (p.Leu464X) in a region enriched by mutation-associated DNA motifs. The mother transmitted the c.1388del to one child and the c.1390del to two children confirming germinal mosaicism. Allele-specific polymerase chain reaction analysis showed that c.1388del is the predominant mutation in lymphocytes of the index case. Haplotype analysis revealed that both mutant alleles have a common chromosomal origin which is distinct from that of the mother's non-mutant ACVRL1 allele. These distinct mutant alleles in tissues and germline could have arisen by DNA structure-mediated events occurring in the early stages of the mother's embryogenesis, prior to the segregation of her germline, which ultimately led to the independent transmission of each allele. These highlight the complexity of genomic events occurring during early embryogenesis and the consequences of mutational mosaicism upon pathogenic variability.

Activin Receptors, Type II/genetics , Alleles , Germ-Line Mutation , Hypertension, Pulmonary/genetics , Mosaicism , Telangiectasia, Hereditary Hemorrhagic/genetics , Adult , Base Sequence , Exons , Familial Primary Pulmonary Hypertension , Female , Haplotypes , Humans , Hypertension, Pulmonary/complications , Pedigree , Telangiectasia, Hereditary Hemorrhagic/complications
Arthritis Rheum ; 62(10): 3093-100, 2010 Oct.
Article En | MEDLINE | ID: mdl-20556823

OBJECTIVE: Pulmonary arterial hypertension (PAH) has emerged as a leading cause of death in systemic sclerosis (SSc). The genetic basis of PAH has been unraveled in recent years, with a major role played by transforming growth factor ß receptors; however, some other candidate genes have also been advocated, including potassium voltage-gated channel, shaker-related subfamily, member 5 (KCNA5). We undertook this study to determine whether KCNA5 polymorphisms confer susceptibility to SSc and its vascular phenotype, including PAH. METHODS: Four KCNA5 single-nucleotide polymorphisms (SNPs), rs10744676, rs1860420, rs3741930, and rs2284136, were genotyped in a discovery set of 638 SSc patients and 469 controls. In addition, rs10744676 was genotyped in an independent replication sample (938 SSc patients and 564 controls) and in a cohort of 168 patients with different PAH subtypes. RESULTS: The KCNA5 rs10744676 variant was found to be associated with SSc in the discovery sample, with an odds ratio (OR) of 0.62 (95% confidence interval [95% CI] 0.48-0.79, adjusted P = 0.0003) in comparison with controls (C allele frequency 11.4% versus 17.2%). When subphenotypes were investigated, an association was found solely for PAH associated with SSc (OR 0.31 [95% CI 0.13-0.71], adjusted P = 0.04). The other KCNA5 SNPs tested were not associated with any SSc subset. The above association with PAH associated with SSc was replicated in the second set. In the combined population, rs10744676 was strongly associated with PAH associated with SSc in comparison with controls (OR 0.36 [95% CI 0.21-0.63], P = 0.0002). In the independent cohort of patients with PAH, after investigating PAH subtypes, only rs10744676 showed an association with PAH associated with SSc. CONCLUSION: Our results provide the first evidence for an association between the KCNA5 rs10744676 variant and PAH associated with SSc.

European Continental Ancestry Group/genetics , Hypertension, Pulmonary/complications , Hypertension, Pulmonary/genetics , Kv1.5 Potassium Channel/genetics , Polymorphism, Single Nucleotide , Scleroderma, Systemic/complications , Scleroderma, Systemic/genetics , Adult , Aged , Case-Control Studies , Europe , Female , Genetic Predisposition to Disease/genetics , Humans , Male , Middle Aged , Odds Ratio
Eur Respir Rev ; 18(111): 42-6, 2009 Mar.
Article En | MEDLINE | ID: mdl-20956122

A 29-yr-old patient with hereditary haemorrhagic telangiectasia was referred to the present authors' centre with progressive exertional dyspnoea. Pulmonary arterial hypertension (PAH) was suspected on Doppler echocardiography and confirmed by right heart catheterisation demonstrating severe PAH. Genetic analysis found an activin receptor-like kinase-1 gene missense mutation. Chest radiography and computed tomodensitometry of the chest revealed a pulmonary arteriovenous malformation with a 5-mm diameter feeding artery in the right lower lobe. Embolisation of the arteriovenous malformation was discussed, but was considered a very high-risk procedure that could aggravate PAH and was therefore not performed. Haemodynamics were improved by dual endothelin receptor antagonist and inhaled iloprost but the patient subsequently died suddenly of a rupture of the arteriovenous malformation into the pleural cavity. Severe PAH is generally considered a contraindication to performing pulmonary arteriovenous malformation embolisation because of the risk of worsening of PAH. However, given the significant risk of rupture, paradoxical embolism and haemoptysis, and the lack of data regarding the evolution of pulmonary pressure after embolisation in PAH, pulmonary arteriovenous malformation embolisation should not be absolutely contraindicated and might be considered in patients with stable PAH.

Arteriovenous Malformations/therapy , Hypertension, Pulmonary/complications , Pulmonary Artery/abnormalities , Pulmonary Veins/abnormalities , Telangiectasia, Hereditary Hemorrhagic/complications , Adult , Embolization, Therapeutic , Fatal Outcome , Female , Humans , Rupture, Spontaneous