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Published ahead of print on November 21, 2002, doi:10.1164/rccm.200208-861OC
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American Journal of Respiratory and Critical Care Medicine Vol 167. pp. 889-894, (2003)
© 2003 American Thoracic Society

Case Report

Pulmonary Veno-occlusive Disease Caused by an Inherited Mutation in Bone Morphogenetic Protein Receptor II

James R. Runo, Cindy L. Vnencak-Jones, Melissa Prince, James E. Loyd, Lisa Wheeler, Ivan M. Robbins, Kirk B. Lane, John H. Newman, Joyce Johnson, William C. Nichols and John A. Phillips, III

Division of Allergy, Pulmonary and Critical Care, Department of Medicine and Departments of Pathology and Pediatrics and Genetic Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; and Division of Human Genetics, Children's Hospital Medical Center, Cincinnati, Ohio

Correspondence and requests for reprints should be addressed to James R. Runo, M.D., Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, T-1217 Medical Center North, Nashville, TN 37232-2650. E-mail: james.runo{at}mcmail.vanderbilt.edu

ABSTRACT

Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary hypertension in which the vascular changes originate in the small pulmonary veins and venules. The pathogenesis is unknown and any link with primary pulmonary hypertension (PPH) has been speculative. Mutations in the bone morphogenetic protein receptor II (BMPR2) gene have been identified in at least 50% of familial cases and in 25% of sporadic cases of PPH. We report a patient with documented PVOD whose mother had severe pulmonary hypertension. Sequencing of the patient's BMPR2 coding region revealed a del44C mutation in Exon 1 that is predicted to encode for a truncated protein. Analysis of DNA from family members suggests that this mutation was transmitted by the proband's mother to two of her four children. The finding of PVOD associated with a BMPR2 mutation reveals a possible pathogenetic connection with PPH.

Key Words: primary pulmonary hypertension • pulmonary hypertension • pulmonary veno-occlusive disease • genetic mutation • bone morphogenetic protein receptor II

Pulmonary veno-occlusive disease (PVOD) is a rare disorder of unknown etiology. It has a similar clinical presentation to primary pulmonary hypertension (PPH) with progressive dyspnea and elevated pulmonary artery pressure (1, 2). The primary pathologic lesion in PVOD is obliteration of the small pulmonary veins and venules from intimal fibrosis and thrombosis (3, 4). Other findings include secondary medial hypertrophy of pulmonary arteries, alveolar hemorrhage, and absence of plexiform lesions (3, 4). In 1998, PVOD was classified under postcapillary causes of pulmonary hypertension (5).

The prevalence of PVOD on biopsies from patients with unexplained pulmonary hypertension is around 5% (6, 7). Chest radiographs may occasionally distinguish PVOD from PPH by the presence of peripheral interstitial infiltrates or septal lines (1, 2). Chest computed tomography can display interlobular septal thickening, mosaic ground-glass opacification, effusions, and mediastinal lymphadenopathy (1, 2, 8, 9). Although there are reports of successful treatment of PVOD with calcium channel blockers or epoprostenol, fulminant pulmonary edema and death have also been reported, and, in general, medical therapy is ineffective (2, 10).

In this study, we report a novel mutation in Exon 1 of the bone morphogenetic protein receptor II (BMPR2) gene, a member of the transforming growth factor-ß receptor family, producing histopathologically proven PVOD. Interestingly, we found that this mutation may have been transmitted by the mother to the proband and one other of her four children. As mutations in transforming growth factor-ß receptors have also been found to cause PPH (11, 12) and hereditary hemorrhagic telangiectasia (13–15), this discovery expands the role of transforming growth factor-ß receptor family mutations in the etiology of vascular disorders.

CASE HISTORY

The proband initially presented at age 36 with dyspnea. Physical examination revealed clear lung fields, elevated jugular venous pressure, a prominent second heart sound, and no digital clubbing. Chest radiography was remarkable for prominence of pulmonary arteries (Figure 1) . Pulmonary function tests revealed normal spirometry and lung volumes with a mild reduction in the diffusing capacity for carbon monoxide. Chest computed tomography demonstrated diffuse, bilateral, mild centrilobular ground glass opacities, and thickened interlobular septae (Figure 2) . Ventilation/perfusion lung scan was normal. An echocardiogram and tests for disorders associated with secondary pulmonary hypertension were not revealing. At right heart catheterization, the mean pulmonary artery pressure was 53 mm Hg with a pulmonary arterial occlusion pressure of 10 mm Hg. The disease was initially thought to be PPH (16), but open lung biopsy revealed findings consistent with PVOD (Figure 3) . The patient has responded to epoprostenol (prostacyclin) and remained stable for the last 5 years, a response that is uncommon but has been recognized (17).



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  		Figure 1. Posterior–anterior chest radiograph of proband. There is enlargement of the right atrium and prominent main pulmonary arteries. Lung fields are clear except for mild interstitial markings. A tunneled catheter is in place for epoprostenol infusion.

 


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  		Figure 2. Chest computed tomogram of proband. The pulmonary parenchyma displays evidence of mild accentuation of the interlobular septae and areas of atelectasis in the bases.

 



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  		Figure 3. (A) A pulmonary venule is virtually completely occluded by spindle cells, representing intimal proliferation. The characteristic single elastic lamina shows a mild degree of reduplication. (B) Another pulmonary venule displays occlusion of the lumen by intimal proliferation. The adjacent alveolar spaces are filled with hemorrhage. Movat stains; original magnification x62.5.

 
The patient's mother died in 1979 of complications caused by right heart failure, and a postmortem examination was not conducted. The clinical diagnosis of pulmonary hypertension was confirmed by a right heart catheterization revealing a mean pulmonary artery pressure of 92 mm Hg, absence of thromboembolic disease by pulmonary angiography, and no evidence of secondary etiologies. Because lung biopsy and autopsy were not performed, it is unknown if the mother's pulmonary hypertension was from PPH or PVOD.

METHODS

Blood samples were acquired from five maternal aunts and uncles, the proband, her father, and three sibs. DNA was isolated by a PUREGENE kit from Gentra Systems (Minneapolis, MN) according to the manufacturer's protocol for whole blood samples. DNA concentrations were determined using a Hoefer DyNAquant fluorometer (Amersham Biosciences, Piscataway, NJ). The Institutional Review Board at Vanderbilt University Medical Center approved the protocol, and consent was obtained from all the family members involved.

Amplicons containing Exon 1 of the BMPR2 gene were amplified by polymerase chain reaction (PCR) from 200 ng of genomic DNA from all family members using PCR SuperMix High Fidelity (Invitrogen, Carlsbad, CA) and 0.2 µM of each oligonucleotide primer. The sequences for the forward and the reverse primers are 5'-AACTAGTTCTGACCCTCGCCCC-3' and 5'-GGACGCATGGCGAAGGGCAA-3', respectively (12). The PCR reaction mixture was denatured for 30 seconds at 94°C and cycled 35 times (94°C, 30 seconds; 69°C, 30 seconds; 68°C, 1 minute), followed by a 10-minute extension at 68°C. The resulting amplicons were 602 base pairs in length. Amplicons from the proband were subcloned using the TOPO TA Cloning kit (Invitrogen) according to the manufacturer's instructions, and positive clones were selected by blue-white color screening. DNA sequence determination of the clones was performed by cycle sequencing using Big Dye terminators (Applied BioSystems, Foster City, CA), and sequencing products were detected with an ABI model 310 Genetic Analyzer.

The del44C mutation was found to destroy an Nco I restriction endonuclease site (5'-CCATGG-3') that was used to confirm segregation of the mutation within the family. Family members' DNAs were amplified by PCR using the same primers and protocol as given previously. Aliquots of the PCR products were digested with Nco I (New England Biolabs, Beverly, MA) at 37°C for 2 hours. The digested amplicons were separated on a 2% agarose gel (BMA, Rockland, ME) and visualized by ethidium bromide staining.

Genotypes were determined for four polymorphic dinucleotide loci closely flanking the BMPR2 locus (D2S311–D2S116–BMPR2–D2S307–D2S369) by PCR amplification using fluorescent-labeled primers (HEX, FAM, or TET). All PCR amplifications were performed in 15-µl reaction volumes and included an initial denaturation at 94°C for 6 minutes and a final extension at 72°C for 10 minutes. For marker D2S116, amplification conditions included 25 cycles at 94°C for 1 minute, 58°C for 1 minute, and 72°C for 30 seconds. Amplification conditions for all other markers were 35 cycles at 94°C for 1 minute, 55°C for 1 minute, and 72°C for 1 minute. Amplicons were subjected to 5% polyacrylamide denaturing gel electrophoresis on an ABI-377 DNA sequencer and analyzed using GeneScan software.

RESULTS

Histology
The histopathologic findings were characteristic of PVOD (Figure 3). Occlusive intimal proliferation was observed in virtually all small veins (< 100 µm), with extensive associated intra-alveolar hemorrhage and numerous aggregates of intra-alveolar hemosiderin-laden macrophages. Larger veins were unaffected. Medium-sized and small arteries were characterized by mild medial thickening with occasional reduplication of elastic laminae, characteristic of Heath and Edwards Grade I arterial changes; neither arterial intimal (plexiform) lesions nor any intra-arterial or intravenous thrombi were noted. Arterial changes were interpreted as secondary to the much more severe small vein occlusive lesions. Capillaries and interstitium were structurally unremarkable.

Genetics
Figure 4 shows the pedigree of the proband (III-3). Sequencing of the proband's BMPR2 coding region identified a deletion of a cytosine residue 44 bases from the translation start site in Exon 1 (del44C) (Figure 5) . This alteration results in a frameshift mutation predicted to cause premature termination of the protein 30 codons downstream (Figure 6) . Because the truncated BMPR2 protein is predicted to contain only a segment of the extracellular domain, it is unlikely to be expressed on the cell surface. Thus, this mutation may cause PVOD by haploinsufficiency or, possibly, dominant-negative effects analogous to those proposed for BMPR2 mutations in PPH (16, 18).



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  		Figure 4. Top: Family pedigree of proband (III-3). Circles and squares represent females and males, respectively. Open symbols indicate unaffected family members, the dashed symbol (III-2) indicates an obligate carrier of mutation, and closed symbols represent affected individuals with pulmonary hypertension. Deceased family members are marked by diagonal lines. Underneath each individual are their haplotypes with the maternal haplotype first (see table below); * indicates the haplotype carrying the del44C bone morphogenetic protein receptor II (BMPR2) mutation. For those family members for whom no DNA samples were available for analysis, the haplotypes have been inferred (see parentheses) on the basis of Mendelian inheritance. Of note, the assignment of haplotypes to the grandparents (I-1 and I-2) was random as either of them may have passed on the mutant haplotype. Middle: Digestion patterns of amplicons generated by polymerase chain reaction of DNAs from family members after digestion with Nco I restriction endonuclease and electrophoresis on 2% agarose gel stained with ethidium bromide. Patterns correspond to individuals in the above pedigree; the proband's mother (II-5) did not have a sample for analysis and thus the lane beneath her is empty. In the heterozygous state, because the mutation del44C destroys an Nco I restriction endonuclease site, it is detected by the undigested amplicon at 602 base pairs (bp). DNAs with 602 and 467 bp fragments are therefore heterozygous for the mutant and normal allele. The bands at the far left of the gel are a standard DNA ladder (Low Biomarker, Bioventures, Murfreesboro, TN) with their sizes listed to the left. Bottom: Table listing the haplotypes in this family for four polymorphic dinucleotide loci flanking the BMPR2 locus (D2S311–D2S116–BMPR2–D2S307–D2S369).

 


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  		Figure 5. Electropherograms obtained for Exon 1 of BMPR2 from C/C, C/{Delta}C, and {Delta}C templates. C/C represents the sequence of two wild-type alleles from an individual without the mutation. The arrow identifies the C immediately preceding the C at position 44 from the start of translation. C/{Delta}C represents the sequencing of the proband's Exon 1 alleles with C indicating the wild-type allele and {Delta}C the deletion of the C at position 44. Deletion of C 44 in the C/{Delta}C sample disrupts the downstream pattern because of the frameshift of base residues in the mutant allele compared with the wild-type allele. This accounts for the presence of two peaks at the majority of locations after the deletion. {Delta}C is the sequence for the cloned mutation from the proband. As only amplicons from the mutant allele are present, disruption of sequencing after the C deletion is not observed. A = adenine; C = cytosine; G = guanine; N = undetermined base residue by ABI sequencer; T = thymine.

 


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  		Figure 6. Functional domains of BMPR2. Exons encoding for the specific functional domains are listed from the 5' end to the 3' end of the DNA sequence. The del44C mutation occurs in Exon 1, 44 bases from the start of translation and results in a frameshift of the coding sequence. A stop codon is produced 30 codons downstream predicting a truncated, nonfunctional protein.

 
Screening DNAs of other family members for the del44C mutation was facilitated by its destroying a restriction site for Nco I. Unfortunately, no DNA was available from the proband's mother or maternal grandparents. Surprisingly, the del44C mutation was not found on examination of DNA from three maternal aunts and two maternal uncles even though the three maternal aunts and one of the maternal uncles share the same BMPR2 haplotype as the proband. Moreover, the only sib (III-2) of the proband who shares the same BMPR2 haplotype is also heterozygous for the del44C mutation (Figure 4) and is not known to have pulmonary hypertension. These findings suggest that a de novo mutation occurred in a gamete of one of the maternal grandparents to create the del44C mutation in the mother of the proband. Supporting this, the mutation was inherited by the proband and one of her three sibs.

DISCUSSION

Little is known regarding the pathogenesis of PVOD or why the disease is localized to pulmonary veins and venules. Proposed etiologies have included immune complex deposition (19), viruses (20, 21), collagen vascular diseases (22, 23), hematologic malignancies (24), bone marrow transplantation (25, 26), radiation therapy (27), and chemotherapy (28). Association of PVOD in sibs has been reported in three families (3, 29–31), but, because vertical transmission was not detected, genetic etiologies have not been investigated.

Recently, germline mutations in the coding region of BMPR2 were discovered in 50% of familial and at least 25% of sporadic cases of PPH (32). We report here a patient with biopsy-proven PVOD with a del44C mutation in BMPR2 that is predicted to encode a truncated, nonfunctional protein. This is the first description of a BMPR2 mutation causing disease other than PPH. The presence of a BMPR2 mutation in PVOD suggests that PPH and PVOD may be different phenotypic manifestations of a defect in BMPR2, and individuals may develop proliferation and remodeling in different locations of the pulmonary vascular bed on the basis of contributing modifier genes and environmental exposures. This may also explain the venous changes noted in some patients with PPH (33). However, due to the proband's reclassification as PVOD, no PPH cases have been associated with a del44C mutation, and it is unknown if this specific mutation only predisposes to PVOD. Many PVOD cases could have an unrecognized genetic basis due to its low prevalence in combination with inadequate family histories. Indeed, this scenario has already been observed in PPH (34–36).

Although DNA of the proband's mother was not available to examine for the presence of a del44C mutation, the absence of the mutation in the mother's four sibs who share the same, exact BMPR2 haplotype makes it improbable that the mutation was constitutive and present in the maternal grandparents. Because the proband and her sister share the same BMPR2 haplotype that carries the del44C mutation, they must have inherited the mutation from their mother. Single paternity is assured in the proband's generation because there are no extraneous haplotypes. Given the estimated penetrance of only 10 to 20% for developing PPH for individuals carrying a BMPR2 mutation (36), it is plausible that BMPR2 mutations causing PVOD might also have decreased penetrance. This would explain why the proband's sister is unaffected.

If the mother did have the del44C mutation, then it likely occurred de novo in one of her parent's gametes as none of her sibs inherited the mutation. De novo mutations have been found in patients with sporadic PPH (32), and theoretically they must have arisen in all familial forms at one point in the pedigree. However, no BMPR2 mutations have been found in over 400 normal chromosomes, and thus de novo BMPR2 mutations are probably not common occurrences (11, 12).

Because no lung biopsy or autopsy was performed, we could not verify histologically that the mother had PVOD. The accessible clinical information supports the mother as having a primary pulmonary vascular process, but whether she had PPH, PVOD, or another form of pulmonary arterial hypertension cannot be discerned. Even if the mother had PPH instead of PVOD, it is likely that her disease is related to her daughter's. Thus, our data indicate that mutations in BMPR2 may predispose to the development of either PPH or PVOD. Due to the rarity of PVOD, and the difficulty in distinguishing PVOD from PPH without biopsy, this association could be easily overlooked. In fact, our patient was initially classified as having PPH (16) until review of her biopsy definitively revealed PVOD.

Given its similar clinical characteristics to PPH and pathologic involvement limited to the pulmonary vascular bed, it is not surprising that the pathogenesis of PVOD may be akin to PPH. The loss of one BMPR2 allele may reduce or nullify antiproliferative effects of bone morphogenetic protein, the major ligand of BMPR2 (37, 38), leading to postcapillary obstruction in PVOD and precapillary obstruction in PPH. This may occur due to haploinsufficiency from the loss of one BMPR2 allele or due to a dominant-negative effect (16, 18).

In summary, mutations in BMPR2 now appear to cause PVOD in addition to familial PPH and some cases of sporadic PPH. Thus, the molecular alterations associated with BMPR2 mutations may exhibit phenotypic heterogeneity, the ability of an allelic mutation at a single locus to produce more than one expression of disease. PVOD and PPH may well represent different ends of the spectrum of the same disease. Future investigations will address if BMPR2 mutations are present in other PVOD cases to delineate genetic versus environmental etiologies of this disease. Because the transforming growth factor-ß receptor family is intimately entwined in the etiologies of various vascular disorders, defining the fundamental molecular defects may aid in our understanding of multiple disease processes and future, targeted therapies.

Acknowledgments

The authors would like to thank E. Wesley Ely, M.D. and Aneysa Sane, M.D. for initial referral of the proband to our Familial PPH registry. Finally, and most importantly, the authors would like to recognize all the family members who provided DNA samples and historical information.

FOOTNOTES

Supported in part by the grants HL 48164 (J.E.L.), Training Grant HL 07123 (J.R.R.), and RR00095 (J.A.P.) from the National Institutes of Health.

Received in original form August 13, 2002; accepted in final form November 19, 2002

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G. Simonneau, N. Galie, L. J. Rubin, D. Langleben, W. Seeger, G. Domenighetti, S. Gibbs, D. Lebrec, R. Speich, M. Beghetti, et al.
Clinical classification of pulmonary hypertension
J. Am. Coll. Cardiol., June 16, 2004; 43(12_Suppl_S): 5S - 12S.
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G. G. Pietra, F. Capron, S. Stewart, O. Leone, M. Humbert, I. M. Robbins, L. M. Reid, and R. M. Tuder
Pathologic assessment of vasculopathies in pulmonary hypertension
J. Am. Coll. Cardiol., June 16, 2004; 43(12_Suppl_S): 25S - 32S.
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M. J. Tobin
Chronic Obstructive Pulmonary Disease, Pollution, Pulmonary Vascular Disease, Transplantation, Pleural Disease, and Lung Cancer in AJRCCM 2003
Am. J. Respir. Crit. Care Med., January 15, 2004; 169(2): 301 - 313.
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P. N. Kao and J. L. Faul
Emerging therapies for pulmonary hypertension: Striving for efficacy and safety
J. Am. Coll. Cardiol., June 18, 2003; 41(12): 2126 - 2129.
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