Clinical reportPulmonary arterial hypertension and portal hypertension in a patient with hereditary hemorrhagic telangiectasiaHipertensión arterial pulmonar e hipertensión portal en un paciente con telangiectasia hemorrágica hereditaria
Introduction
Pulmonary arterial hypertension (PAH) is a rare disease with a complex pathogenesis that may be heritable, idiopathic or associated with other diseases, drugs or toxics and possibly influenced by genetic factors. Group I of the Nice classification includes idiopathic and hereditary forms and others associated to connective tissue diseases, portal hypertension, HIV infection, schistosomiasis and congenital heart diseases.1 More than 70% of the hereditary cases are carriers of mutations in the gene that codifies for the Bone morphogenetic protein receptor type 2 (BMPR2). Although familial individuals of a PAH patient with a BMPR2 mutation and carrying the mutation have a risk to develop the disease of around 20%, indicating that more than a single mutation is necessary to develop PAH, perhaps other genetic or exogenous factors play a role.2 Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder with a prevalence of approximately 10 cases per 100,000 inhabitants. HHT is characterized by the presence of epistaxis, mucocutaneous telangiectasias and lung, brain and liver vascular malformations. PAH is a rare complication of HHT, which happens in less than 1% of the cases but implies a marked worsening of prognosis. The genes of Activin receptor like kinase 1 (ACVRL1) and Endoglin (ENG) seem to have an important role in its pathogenesis.3 Liver cirrhosis with portal hypertension is also associated with the presence of PAH in 1–2% of cases 4. We present a patient with HHT and liver cirrhosis with portal hypertension that developed PAH. Likely, the interaction between all of these factors favors the appearance of PAH.
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Case report
A 62-year-old male was sent to our Unit of PAH because of dyspnea on exertion and suspicion of PAH in an echocardiographic study. He was diagnosed 25 years before of HHT with spontaneous and very frequent nose bleeds, chronic iron deficiency anemia and multiple cutaneous and digestive telangiectasias, including esophagus, stomach and colon, with several episodes of gastrointestinal bleeding. He had no known family history of the disease and only a healthy daughter. In 1981, a secundum atrial
Results
After informed consent, we conducted a genetic study that included BMPR2, ACVRL1, ENG and KCNA5 (voltage-gated potassium channel) genes. PolyPhen, Sift and pMUT informatics programs were used to evaluate the potential pathogenicity in the case of missense mutations and NNSplice and NetGene to test their possible involvement in splicing. In BMPR2 gene we found a potentially pathogenic missense mutation, c.1021G>A (V341L), and one synonymous mutation, c.327G>A (p.Q109Q), which could affect
Discussion
This case illustrates the complexity of the pathogenesis of PAH. Although there are other diseases, toxic, drugs or genetic alterations associated with this disease, none by itself seems to be sufficient to develop it. HHT is a relatively common disease, but the presence of PAH occurs in no more than 1% of all patients. Portal hypertension also has a high prevalence but the risk of clinically relevant PAH is probably less than 2%. BMPR2 mutations, the most important genetic alteration
Conflict of interest
A. Baloira has participated as a consultant for Actelion, GSK, Ferrer and Pfizer and has received research grants from Actelion.
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