Elsevier

Medicina Clínica

Volume 144, Issue 6, 15 March 2015, Pages 261-264
Medicina Clínica

Clinical report
Pulmonary arterial hypertension and portal hypertension in a patient with hereditary hemorrhagic telangiectasiaHipertensión arterial pulmonar e hipertensión portal en un paciente con telangiectasia hemorrágica hereditaria

https://doi.org/10.1016/j.medcli.2014.09.024Get rights and content

Abstract

Background and objective

Pulmonary arterial hypertension (PAH) is a rare disease that could be inherited with an autosomal dominant pattern. Mutations in BMPR2 gene are described in over 70% of cases, although other genes are involved in lesser extend in PAH. Hereditary hemorrhagic telangiectasia (HHT) is another rare autosomal dominant disease. PAH is a rare complication of HHT that occurs in less than 1% of cases. Liver cirrhosis with portal hypertension is also associated with the presence of PAHs in 1–2% of cases.

Patients

We present here a patient with HHT who developed PAH shortly after showing portal hypertension.

Results

Some genes (BMPR2, ACVRL1, ENG) seem to play an important role in PAH pathogenesis. We analyzed these genes, detecting mutations in BMPR2 gene (c.1021G>A (V341L), c.327G>A (p.Q109Q)), ACVRL1 (c.313+20C>A, c.1502+7A>G) and ENG (c.498G>A (Q166Q)). The patient also had 3 polymorphisms in the TRPC6 gene (c.1-361A>T, c.1-254C>G, c.1-218C>T).

Conclusions

The study of these genes will help us to identify and track individuals susceptible for developing PAH associated with other diseases.

Resumen

Fundamento y objetivo

La hipertensión arterial pulmonar (HAP) es una enfermedad rara que en la forma hereditaria se expresa como una afección autosómica dominante. Las mutaciones en el gen BMPR2 son características en más del 70% de los casos, y otros genes están envueltos en la compleja patogénesis de la HAP. La telangiectasia hemorrágica hereditaria (THH) es otra enfermedad rara autosómica dominante. La HAP es una complicación rara de la THH que ocurre en menos del 1% de los casos. La cirrosis hepática con hipertensión portal también se asocia con la presencia de HAP en el 1–2% de los casos.

Pacientes

Presentamos un paciente con THH que desarrolló HAP poco tiempo después de presentar hipertensión portal.

Resultados

Varios genes (BMPR2, ACVRL1, ENG) parecen tener un papel importante en su patogénesis. Se estudiaron a nivel molecular los cambios en estos genes, encontrándose mutaciones en el gen BMPR2 (c.1021G>A (V341L), c.327G>A (p.Q109Q)), ACVRL1 (c.313+20C>A, c.1502+7A>G) y ENG (c.498G>A (Q166Q)). El paciente también presenta 3 polimorfismos en el gen TRPC6 (c.1-361A>T, c.1-254C>G, c.1-218C>T).

Conclusiones

El estudio de estos genes nos ayudará a definir y seguir los individuos susceptibles de desarrollar HAP asociada a otras enfermedades.

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.

Section snippets

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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