Diagnosis and Treatment of Pulmonary Hypertension by Yoshihiro Fukumoto

Author:Yoshihiro Fukumoto
Language: eng
Format: epub
Publisher: Springer Singapore, Singapore

9.3 Clinical Phenotype

It has been known that 6 % of PAH patients reported a family history of PAH in the prospective National Institutes of Health registry [19]. However, in the 4th PH World Symposium (Dana Point, 2008) [9], the term familial PAH was replaced with HPAH, because 10–40 % of cases previously thought to be IPAH have BMPR2 mutations, and this may pose a hereditary risk to other family members [20]. These findings may be related to the fact a family history of PAH may be unrecognized in IPAH cases with BMPR2 mutations, as a consequence of either undiagnosed disease, incomplete penetrance, or de novo mutations. In patients with PAH associated with other conditions, approximately 20 % of ALK1 mutation carriers were found in anorexigen-induced PAH [21, 22]. However, BMPR2 mutations are not found in PAH patients associated with scleroderma or other connective tissue diseases, portal hypertension, or human immunodeficiency virus infection, except for some reports in CHDs [23]. Familial cases of pulmonary veno-occlusive diseases are rarely associated with a BMPR2 mutation [24].

Heritable PAH patients with BMPR2 mutations have an earlier age of onset and a more severe hemodynamic impairment at diagnosis. Patients with HPAH had higher mean pulmonary artery pressure, higher pulmonary vascular resistance, lower cardiac index, and worse survival, while such patients are more likely to be treated with parenteral epoprostenol or lung transplant [25, 26]. Both children and adults with PAH and BMPR2 mutations are less likely to respond to acute vasodilator testing and are unlikely to benefit from treatment with calcium channel blockade [27, 28]. Symptomatic HPAH patients with ALK1 mutations are associated with an earlier age of onset and more rapid disease progression than HPAH patients with BMPR2 mutations, although ALK1-positive patients had better hemodynamic status at diagnosis, but none responded to acute vasodilator challenge [29]. PAH patients carrying ALK1 mutations may develop both PAH and HHT. Since HHT has nearly complete penetrance at the age of 60 years, clinical symptom of HHT may be absent in ALK1 mutation carriers in the childhood or early adulthood.

Recent epidemiological data no longer support genetic anticipation in BMPR2-related familial PAH [30]. Analysis of families with sibships that have lived at least 57 years from first family diagnosis allows >85 % of mutation carriers to express disease. In these families, the apparent effect of lower age of onset in earlier generations disappears, because the time it takes for penetrance to occur in this illness can be up to 75 years of age in an apparently unaffected carrier. Furthermore, the usual genetic mechanisms for anticipation, trinucleotide repeat expansions, are not present in BMPR2 [30].

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