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* From the Department of Pulmonary, Allergy, and Critical Care Medicine (Dr. Minai), Cleveland Clinic, Cleveland, OH; Genomic Medicine Institute (Ms. Rigelsky), Lerner Research Institute, Cleveland, OH; Cleveland Clinic Genomic Medicine Institute (Dr. Eng), Cleveland, OH; Division of Pulmonary, Critical Care, and Sleep Medicine (Dr. Arroliga), Scott and White Clinic, Temple, TX; and Cleveland Clinic Lerner College of Medicine (Dr. Stoller), Cleveland Clinic, Cleveland, OH.
Correspondence to: Omar A. Minai, MD, FCCP, Department of Pulmonary, Allergy, and Critical Care Medicine, A90, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195; e-mail: minaio{at}ccf.org
Abstract
Hereditary hemorrhagic telangiectasia (HHT) may be associated with pulmonary hypertension (PH). In the context that little attention has been given to long-term follow-up of such individuals, we report a patient with PH associated with HHT with special attention to clinical features and long-term response to therapy. To our knowledge, this case represents only the second with a 10-year follow-up reported and demonstrates that aggressive therapy can lead to long-term improvement in clinical parameters and survival.
Key Words: genetic • hereditary hemorrhagic telangiectasia • pulmonary hypertension • pulmonary vascular disease • shunt
Since the association between pulmonary hypertension (PH) and hereditary hemorrhagic telangiectasia (HHT) was first recognized by Trembath et al1 and Harrison et al,2 much attention has focused on germ line mutations of activin receptor-like kinase type 1 (ALK1/ACVRL1), which encodes a member of the transforming growth factor (TGF)-ß receptor family, as a causal link. Less attention has been given to the natural history of patients with both PH and HHT, particularly those managed with vasoactive medications. The current report extends the sparse available long-term experience by presenting the case of a 24-year-old woman with PH and a clinical diagnosis of HHT we followed up over 10 years on a variety of vasoactive medications.
Case History
At presentation in 1995, our patient was a previously healthy 24-year-old woman with dyspnea that began during the seventh month of her first pregnancy and worsened significantly thereafter, causing her to seek attention 7 months postpartum. She had been adopted at age 8 years, and had no knowledge of her birth parents. She had previously enjoyed good health save for an initial episode of minor epistaxis at age 20 years, which recurred yearly thereafter, but no hemoptysis, GI bleeding, or neurologic symptoms.
Her initial physical examination in May 1995 showed clear lung fields, a loud P2, grade 2/6 systolic ejection murmur, a parasternal heave, and congestive hepatomegaly. Laboratory assessment included a chest radiograph showing cardiomegaly (Fig 1 ), a ventilation-perfusion scan that showed multiple subsegmental mismatched perfusion defects, and a transthoracic echocardiogram showing a dilated right ventricle, moderate tricuspid regurgitation, an estimated right ventricular systolic pressure of 106 mm Hg, and no right-to-left shunt. Pulmonary function testing showed normal FEV1, FVC, FEV1/FVC, and normal lung volume measurements but a decreased diffusion capacity of the lung for carbon monoxide (59% of predicted). A pulmonary angiogram showed no evidence of acute or chronic pulmonary emboli and no evidence of arteriovenous malformations (AVMs) at that time.
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Discussion
The current case extends available experience with PH and HHT in several ways. First, in contrast to the now well-recognized association of HHT and PH mediated by mutations of ALK1/ACVRL1,2 our patient has a clinical diagnosis of HHT (including epistaxis, mucocutaneous telangiectasia, and pulmonary AVMs) without a detectable ALK1/ACVRL1 or ENG abnormality. Experience with this patient demonstrates that not all patients with HHT have an identifiable mutation in the ENG or ALK1/ACVRL1 genes. In considering reasons that a known mutation was not detected, it is important to point out that the relative prevalence of ENG and ALK1/ACVRL1 mutations in HHT appears to be region specific.4 Polymerase chain reaction-based direct sequencing of these genes detects approximately 60 to 80% of mutations in individuals with HHT456 but will not detect certain mutations, including large deletions and rearrangements. The latter of these should not account for > 10 to 15% of those with a clinical diagnosis of HHT. The remainder of mutations are probably caused by other genes.7 ALK1/ACVRL1 and ENG, which are associated with HHT, are members of the TGF-ß pathway. ALK1/ACVRL1 encodes the membrane-bound receptor, and ENG encodes endoglin, which is a transmembrane glycoprotein.8 As evidence of the wide impact of the TGF-ß pathway, mutations have been implicated in cancer predisposition syndromes, bone disorders, vascular diseases, and others.48 Indeed, many members of the TGF-ß pathway have dual roles in effecting cell proliferation and suppression.9 Overlapping clinical features have been observed in conditions caused by different genes in the TGF-ß pathway.
As a second extension of available knowledge, our patient has been followed up for 10 years on various vasoactive medications, including nifedipine, epoprostenol and, most recently, IV treprostinil, and has remained clinically stable with good functional status (New York Heart Association class II), stable exercise capacity, and freedom from the need for supplemental oxygen. Indeed, to our knowledge, she represents only the second such patient followed up for an extended interval. Schlag et al10 described the 10-year follow-up of a 49-year old woman with HHT and PH (pulmonary artery pressures at right-heart catheterization, 74/33 mm Hg; mean, 51 mm Hg; Fick cardiac output, 6.4 L/min) who was treated initially with calcium-channel blockers and then inhaled iloprost, beraprost, and finally bosentan. Over the course of her follow-up, her mean pulmonary artery pressure remained stable at approximately 50 mm Hg. To our knowledge, our patient represents only the second patient with HHT and PH to be described with long-term follow-up after treatment with a variety of vasoactive medications. Taken together, these two reports demonstrate the possibility of decade-long survival, clinical stability and, in our patient, even functional and physiologic improvement over the course of treatment. Clearly, longer follow-up of larger cohorts is required before definitive conclusions are possible, but this early experience provides strong rationale for aggressive therapy, most certainly in this special subset of patients with both HHT and PH.
In summary, the current patient extends the sparse clinical experience with patients with PH and HHT by prompting consideration of mediators of vascular abnormality other than the recognized ALK1/ACVRL1 mutations and offers only the second reported instance of 10-year follow-up. Her overall encouraging course should prompt clinicians to remain optimistic about the value of current and emerging therapies for this complex condition, while serving as a reminder of the need for more extensive, long-term study of this patient group. With further molecular understanding of the basis for PH in HHT, specific molecular-targeted therapies can be fashioned. However, such molecular-based therapies need to be mindful of the balance of the TGF-ß and bone morphogenetic protein pathways as they relate to both vascular disease and malignancy.
Footnotes
Abbreviations: AVM = arteriovenous malformation; HHT = hereditary hemorrhagic telangiectasia; PH = pulmonary hypertension; TGF = transforming growth factor
Dr. Eng is a recipient of the Doris Duke Distinguished Clinical Scientist Award, is a National Scholar of the Davis Heart and Lung Research Institute of The Ohio State University, and is an Honorary Fellow of Cancer Research UK Human Cancer Genetics Research Group of the University of Cambridge.
The authors have no personal or financial conflicts of interest with the issues discussed.
Received for publication September 14, 2006. Accepted for publication November 22, 2006.
References
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