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Original Research: Pulmonary Vascular Disease |

EIF2AK4 Mutations in Pulmonary Capillary HemangiomatosisMutations in Pulmonary Capillary Hemangiomatosis FREE TO VIEW

D. Hunter Best, PhD; Kelli L. Sumner, BS; Eric D. Austin, MD; Wendy K. Chung, MD, PhD; Lynette M. Brown, MD, PhD; Alain C. Borczuk, MD; Erika B. Rosenzweig, MD; Pinar Bayrak-Toydemir, MD, PhD; Rong Mao, MD; Barbara C. Cahill, MD; Henry D. Tazelaar, MD, FCCP; Kevin O. Leslie, MD; Anna R. Hemnes, MD; Ivan M. Robbins, MD; C. Gregory Elliott, MD, FCCP
Author and Funding Information

From the Department of Pathology (Drs Best, Bayrak-Toydemir, and Mao) and Department of Medicine (Drs Brown and Elliott), School of Medicine, and Pulmonary Division and Department of Medicine (Dr Cahill), The University of Utah, Salt Lake City, UT; ARUP Institute for Clinical and Experimental Pathology (Drs Best, Bayrak-Toydemir, and Mao and Ms Sumner), ARUP Laboratories, Salt Lake City, UT; Department of Pediatrics (Dr Austin) and Division of Allergy, Pulmonary and Critical Care Medicine (Drs Hemnes and Robbins), Vanderbilt University Medical Center, Nashville, TN; Departments of Pediatrics and Medicine (Drs Chung and Rosenzweig) and Department of Pathology and Cell Biology (Dr Borczuk), Columbia University Medical Center, New York, NY; Department of Medicine (Drs Brown and Elliott), Intermountain Medical Center, Intermountain Healthcare, Murray, UT; and Department of Laboratory Medicine and Pathology (Drs Tazelaar and Leslie), Mayo Clinic Arizona, Mayo Foundation for Medical Education and Research, Scottsdale, AZ.

Correspondence to: C. Gregory Elliott, MD, FCCP, Department of Medicine, Intermountain Medical Center, 5121 S Cottonwood St, #307, Murray, UT 84107; e-mail: greg.elliott@imail.org


For editorial comment see page 197

Funding/Support: This research was supported in part by the National Institutes of Health [K23 HL098743; R01 HL060056; NIH 1P01HL108800-0] and Intermountain Research and Medical Foundation [1007044].

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;145(2):231-236. doi:10.1378/chest.13-2366
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Published online

Background:  Pulmonary capillary hemangiomatosis (PCH) is a rare disease of capillary proliferation of unknown cause and with a high mortality. Families with multiple affected individuals with PCH suggest a heritable cause although the genetic etiology remains unknown.

Methods:  We used exome sequencing to identify a candidate gene for PCH in a family with two affected brothers. We then screened 11 unrelated patients with familial (n = 1) or sporadic (n = 10) PCH for mutations.

Results:  Using exome sequencing, we identified compound mutations in eukaryotic translation initiation factor 2 α kinase 4 (EIF2AK4) (formerly known as GCN2) in both affected brothers. Both parents and an unaffected sister were heterozygous carriers. In addition, we identified two EIF2AK4 mutations in each of two of 10 unrelated individuals with sporadic PCH. EIF2AK4 belongs to a family of kinases that regulate angiogenesis in response to cellular stress.

Conclusions:  Mutations in EIF2AK4 are likely to cause autosomal-recessive PCH in familial and some nonfamilial cases.

Figures in this Article

Pulmonary capillary hemangiomatosis (PCH) is a rare disease characterized by a proliferation of multiple layers of capillaries that expand alveolar septa and often invade bronchial walls and the pleura.1 The disorder is slowly progressive and ultimately fatal. A trial of antiangiogenic therapy followed by lung transplantation is often offered to affected individuals.2,3

Symptoms, including progressive dyspnea, cough, hemoptysis, fatigue, and weight loss, are not specific and mimic other forms of pulmonary arterial hypertension (PAH). Echocardiography and cardiac catheterization may suggest PAH or pulmonary veno-occlusive disease,4,5 and the diagnosis may prove difficult because pathologic examination of lung tissue may show features which suggest pulmonary veno-occlusive disease or pulmonary hemosiderosis.1,6 Furthermore, most patients with symptomatic PAH are not referred for lung biopsy due to risk of the procedure, unless there is a high suspicion of another underlying pathologic condition requiring a different treatment. Thus, PCH can challenge clinicians and pathologists, and the correct diagnosis is often delayed or not made until the time of lung transplant or death.1,6

The cause of PCH remains unknown. Previous investigators have suggested that dysregulated angiogenesis plays a role in the pathogenesis. Prior studies suggest that a variety of angiogenic factors including platelet-derived growth factor,7 basic fibroblast growth factor,8 vascular endothelial growth factor, and Ki-679 may play a role in the pathobiology of PCH.

Although, typically, the family history is unremarkable, there have been reports of familial PCH with multiple affected family members.10,11 Families with affected siblings have suggested an autosomal-recessive mode of inheritance.

We used whole-exome sequencing to identify a novel gene for heritable PCH. We identified pathogenic mutations in eukaryotic translation initiation factor 2 α kinase 4 (EIF2AK4) (formerly known as GCN2) in familial PCH, as well as two cases of PCH without a family history of PCH.

Study Participants

All participants provided written informed consent for genetic studies according to protocols approved by the institutional review boards (IRBs) of the participating institutions (Columbia University IRB #AAAA8979 and #AAAC0884; Intermountain Healthcare Urban Central Region IRB #1007044; Vanderbilt University IRB #9401).

We diagnosed PCH in two male siblings in a family (Fig 1). In 2004, PCH was diagnosed in the first sibling (II.1) at 20 years of age at the time of lung transplantation. Pathologic examination demonstrated extensive proliferation of pulmonary capillaries consistent with PCH (Fig 2). Clinical characteristics are provided in Table 1. In 2012, the second sibling (II.2) was diagnosed with PCH based upon lung biopsy at 33 years of age. The two affected men, their sister, mother, and father provided blood samples from which genomic DNA was extracted. Ten additional patients with pathologically confirmed sporadic PCH and one patient with familial PCH consistent with autosomal-dominant inheritance were sequenced with dideoxy sequencing of all coding exons of EIF2AK4.

Figure Jump LinkFigure 1. Pedigree of family 1. The c.1153dupG mutation and the c.3766C>T mutation segregate with pulmonary capillary hemangiomatosis (PCH) in the index family (family 1). The unaffected mother (I-2) and unaffected daughter (II.3) carried the c.1153dupG mutation, and the unaffected father (I-1) carried the c.3766C>T mutation. (+) denotes wild-type alleles and (-) denotes mutation. →, the proband; ○, unaffected females; ■, affected males; □, unaffected males; /, deceased family members.Grahic Jump Location
Figure Jump LinkFigure 2. PCH of family 1, member II.1, as demonstrated in explanted lung. A, Note the low-power, somewhat nodular, appearance of the areas of increased alveolar thickness (hematoxylin and eosin, original magnification × 40). B, The higher-power image shows that the increased thickness is due to a proliferation of capillaries. Special stains, including elastic stains and the endothelial marker CD31 confirmed this, but are not shown (hematoxylin and eosin, original magnification × 100). C and D, Images are obtained from surgical biopsies of family 1, member II.2 (hematoxylin and eosin, original magnification × 15). C, The thickened septa are less nodular in appearance and, D, somewhat mimic an interstitial pneumonia. Note the thickened pulmonary artery at 12 o’clock (←), a feature typically observed in patients with capillary hemangiomatosis as a manifestation of pulmonary hypertension. See Figure 1 legend for expansion of abbreviation.Grahic Jump Location
Table Graphic Jump Location
Table 1 —Clinical and Molecular Characteristics of Four Patients With PCH and EIF2AK4 Mutations

Dlco = diffusion capacity of lung for carbon monoxide; EIF2AK4 = eukaryotic translation initiation factor 2 α kinase 4; na = not available; PA = pulmonary artery pressure; PCH = pulmonary capillary hemangiomatosis; PCWP = pulmonary capillary wedge pressure; WHO = World Health Organization.

In addition to the pathologic findings, patients diagnosed with PCH had clinical features typical of the disease (Table 1). Presenting symptoms included marked dyspnea, cough, and fatigue. Pulmonary function studies demonstrated severe reduction of single-breath carbon monoxide diffusion capacity, and lung CT scans demonstrated bilateral diffuse nodular opacities. Cardiac catheterization showed pulmonary hypertension with normal pulmonary capillary wedge pressure measurements. In addition, the correct clinicopathologic diagnosis in the proband of family 1 (member II.1), and the proband in the unrelated family,12 was not made until the diseased lungs were removed at the time of lung transplantation, even though both patients had undergone an extensive diagnostic evaluation including open lung biopsies before lung transplantation.

Exome Sequencing

Exome sequencing was performed using samples from the initial two male affected siblings. Exons were captured with the Agilent SureSelect kit (x7 Human all Exon U4; Agilent Technologies Inc) and sequenced with 2 × 100 base pair paired-end reads on an HiSeq2000 according to the manufacturer’s recommendations (Illumina, Inc). Sequence was aligned to Hg19 using the Burrows-Wheeler Aligner (0.5.9),13 and variants were called with the Genome Analysis Toolkit (Version 1.6).14 More than 97% of bases sequenced had a quality score > 10, and variants with a quality score < 10 were removed to avoid false-positives. Given the rarity of PCH, variants that had an allele frequency of > 1% in dbSNP, the 1000 Genomes Project, and the National Heart, Lung, and Blood Institute (NHLBI) Exome Variant Server were filtered out, leaving 792 variants present in at least one of the two brothers. Assuming an autosomal-recessive mode of inheritance, filtering for two shared variants in the two affected brothers reduced the number of variants to 87 and the number of possible genes to 37. Detailed review analysis of the 87 variants in these candidate genes revealed that only a single gene (EIF2AK4) contained two clearly pathogenic mutations.

Sanger Sequencing

Amplicons containing the two mutations in EIF2AK4 in family 1 were amplified and Sanger sequenced in the nuclear members of family 1. To replicate the genetic findings, all coding exons and splice junctions of EIF2AK4 were Sanger sequenced in 11 independent patients with PCH using the BigDye Terminator Cycle Sequencing kit (Applied Biosystems, Life Technologies Corporation) on a 3730 DNA Analyzer (Applied Biosystems, Life Technologies Corporation). Primer sequences are available upon request.

Exome Sequencing

Through our filtering process, we identified a gene (EIF2AK4) containing two novel, clearly pathogenic mutations: c.1153dupG (p.Val385fs) and c.3766C>T (p.Arg1256X) shared by both affected brothers (Fig 1). Both variants were confirmed in each brother by Sanger sequencing. Both unaffected parents were heterozygous carriers of one of the two mutations in EIF2AK4. The mother carried the frameshift mutation, c.1153dupG, and the father carried the nonsense mutation, c.3766C>T. The unaffected sister was heterozygous for c.1153dupG by Sanger sequencing only.

Case Series of Patients

We identified novel EIF2AK4 mutations in two of the 10 additional patients with PCH without a family history (20%). One patient was homozygous for a frameshift mutation c.1392delT (p.Arg465fs). The other patient was a compound heterozygote for a splice mutation (c.860-1G>A) and a nonsense mutation, c.3438C>T (p.Arg1150X). None of the identified mutations in EIF2AK4 (Table 1) were observed in exome data from 112 patients recruited for an unrelated study. We did not identify EIF2AK4 mutations in the proband from a second family, which is affected by PCH due to autosomal-dominant transmission. None of the five EIF2AK4 mutations is present in 1000 Genomes15 or in the available data from the NHLBI Exome Sequencing Project16 (ESP) Exome Variant Server.

We report the identification of a novel gene, EIF2AK4, as a likely cause of autosomal-recessive PCH characterized by proliferation of small pulmonary capillaries. Whole-exome sequencing allowed us to identify two loss-of-function mutations in EIF2AK4 by analyzing only two affected brothers with PCH. We confirmed the role of EIF2AK4 in PCH by identifying two of 10 additional patients with no family history of PCH, each with two clear loss-of-function mutations. Previous reports suggested an autosomal-recessive inheritance pattern in a family affected by PCH.10 Our results provide molecular confirmation of the autosomal-recessive inheritance pattern described by Langleben et al.10

The absence of pathogenic mutations in EIF2AK4 in a patient with familial PCH and in the other eight sporadic cases may reflect mutations in regions of EIF2AK4 that we did not screen (ie, deep intronic regions, regulatory regions, or large exonic deletions/duplications) or more likely there may be additional genetic or nongenetic factors involved in the development of PCH. Etiologic and genetic heterogeneity is common in pulmonary vessel diseases including PAH, a disorder caused predominantly by mutations in bone morphogenetic protein receptor type 2, and rarely caused by mutations in ALK1, CAV1, SMAD9, KCNK3, and likely other undiscovered genes.17 In addition, our initial family has a different mode of inheritance (autosomal recessive) from the second family (autosomal dominant), which may explain the absence of EIF2AK4 mutations in the second family.

PCH is a well-recognized cause of pulmonary hypertension, but this disorder has proven difficult to understand and classify.18 Currently, PCH is classified in diagnostic group 1′ and is combined with pulmonary veno-occlusive disease because the pathologic changes (ie, pulmonary hemosiderosis, interstitial edema, lymphatic dilation, and intimal fibrosis with or without medial hypertrophy in the small pulmonary arteries and/or veins) often overlap those seen with pulmonary veno-occlusive disease.18 Further studies, which include molecular analyses, may enhance the understanding and classification of PCH and possibly pulmonary veno-occlusive disease. However, there has been a paucity of data to date on the genetic and molecular factors causing PCH, hampering efforts to improve classification and to develop specific therapies for this rare disease.

The protein product of EIF2AK4 belongs to a family of kinases that regulates angiogenesis. Specifically, these kinases phosphorylate the α subunit of eukaryotic translation initiation factor 2, a protein that down-regulates protein synthesis in response to varied cellular stresses.19 The α subunit of eukaryotic translation initiation factor 2 plays a critical role in tumor cell adaptations to stressful environments, whereby these cells induce angiogenesis, proliferate, and resist apoptosis.20,21 These properties are compatible with the angiogenic pathology of PCH, a disorder characterized by uncontrolled proliferation of pulmonary microvessels.

The two brothers diagnosed with PCH were found to have the same two pathogenic mutations in EIF2AK4, and yet the age of onset and the severity of the disease differed somewhat. The first brother presented at age 19 years with exertional dyspnea and severe precapillary pulmonary hypertension, having had bronchitis for much of his life. He died after lung transplantation at 20 years of age. His brother also had nonspecific respiratory complaints which began in his late teens. However, he did not present with exertional dyspnea and cough until 33 years of age. Initial evaluation of this brother also showed precapillary pulmonary hypertension, but his disease has progressed more slowly. These observations suggest that other genetic and/or environmental factors may modify the course and severity of PCH associated with pathogenic mutations in EIF2AK4.

If our observations are confirmed and expanded, then genetic counseling and genetic testing may prove helpful to patients and families affected by PCH, just as they have for other heritable disorders, for example, cystic fibrosis. Genetic testing offers the possibility of earlier identification of asymptomatic patients who are at risk to develop PCH, providing opportunities for early interventions to delay the onset or treat heritable PCH. It may also serve as an additional diagnostic tool for select patients with PAH in whom there is a clinical suspicion of PCH.

In conclusion, we identified mutations in EIF2AK4 as a novel genetic cause of PCH for some familial and sporadic patients with PCH. This finding provides a new opportunity to advance our understanding of the pathogenesis of PCH and pulmonary vascular biology.

Author contributions: Drs Best, Brown, and Elliott had full access to all data in the study and take responsibility for the data and the accuracy of the data analysis.

Dr Best: contributed to conception and design; acquisition, analysis, and interpretation of data; drafting of the submitted article; and revising it critically for important intellectual content.

Ms Sumner: contributed to conception and design; acquisition, analysis, and interpretation of data; drafting of the submitted article; and revising it critically for important intellectual content.

Dr Austin: contributed to conception and design; acquisition, analysis, and interpretation of data; drafting of the submitted article; and revising it critically for important intellectual content.

Dr Chung: contributed to conception and design; acquisition, analysis, and interpretation of data; drafting of the submitted article; and revising it critically for important intellectual content.

Dr Brown: contributed to conception and design; acquisition, analysis, and interpretation of data; drafting of the submitted article; and revising it critically for important intellectual content.

Dr Borczuk: contributed to conception and design; acquisition, analysis, and interpretation of data; drafting of the submitted article; and revising it critically for important intellectual content.

Dr Rosenzweig: contributed to conception and design; acquisition, analysis, and interpretation of data; drafting of the submitted article; and revising it critically for important intellectual content.

Dr Bayrak-Toydemir: contributed to conception and design; acquisition, analysis, and interpretation of data; drafting of the submitted article; and revising it critically for important intellectual content.

Dr Mao: contributed to conception and design; acquisition, analysis, and interpretation of data; and approval of the final draft of the submitted article.

Dr Cahill: contributed to conception and design; acquisition, analysis, and interpretation of data; drafting of the submitted article; and revising it critically for important intellectual content.

Dr Tazelaar: contributed to conception and design; acquisition, analysis, and interpretation of data; drafting of the submitted article; and revising it critically for important intellectual content.

Dr Leslie: contributed to conception and design; acquisition, analysis, and interpretation of data; drafting of the submitted article; and revising it critically for important intellectual content.

Dr Hemnes: contributed to conception and design; acquisition, analysis, and interpretation of data; drafting of the submitted article; and revising it critically for important intellectual content.

Dr Robbins: contributed to conception and design; acquisition, analysis, and interpretation of data; drafting of the submitted article; and revising it critically for important intellectual content.

Dr Elliott: contributed to conception and design; acquisition, analysis, and interpretation of data; drafting of the submitted article; and revising it critically for important intellectual content.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Brown is employed by Intermountain Healthcare (IHC Health Services, Inc). In the last 2 years IHC Health Services, Inc has received compensation from Ikaria Inc for a clinical trial contract for which Dr Brown is the principal investigator. In addition, Dr Brown has received compensation for time and travel from United Therapeutics for attendance at advisory board meetings. Dr Elliott is employed by Intermountain Healthcare (IHC Health Services, Inc). In the last 3 years IHC Health Services, Inc has received compensation for clinical trial contracts (on which Dr Elliott is the Principal Investigator) from Actelion Pharmaceuticals Ltd, Bayer Corp, GeNo, Gilead, and United Therapeutics Corp. IHC Health Service Inc has also received or will receive compensation from LungRx for Dr Elliott’s travel and consultancy on the BEAT study. During this same time period, Dr Elliott received compensation for time and travel from Ikaria Inc as chair of the steering committee for the INOPulse study and from Co-Therix as a steering committee member. Dr Rosenzweig has received honoraria for advisory panels from Actelion Pharmaceuticals Ltd and United Therapeutics Corp in the past 3 years and is a consultant for Ikaria, Inc on a clinical research trial. Dr Bayrak-Toydemir is employed by ARUP Laboratories. Dr Hemnes has received research funding from the National Institutes of Health, United Therapeutics Corp, and Pfizer Inc, and has served as a consultant to Actelion Pharmaceuticals Ltd, Pfizer Inc, and United Therapeutics Corp. Drs Best, Austin, Chung, Borczuk, Mao, Cahill, Tazelaar, Leslie, and Robbins and Ms Sumner have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsors had no role in the design of the study, the collection of and analysis of the data, or in the preparation of the manuscript.

Other contributions: We thank the patients and their family members, Jana Johnson; Lisa Wheeler, BS; Patricia Lanzano, BS; Ken Ward, MD; and Lesa Nelson, BS. This work would not have succeeded without their assistance.

EIF2AK4

eukaryotic translation initiation factor 2 α kinase 4

IRB

institutional review board

PAH

pulmonary arterial hypertension

PCH

pulmonary capillary hemangiomatosis

Wagenvoort CA, Beetstra A, Spijker J. Capillary haemangiomatosis of the lungs. Histopathology. 1978;2(6):401-406. [CrossRef] [PubMed]
 
Bartyik K, Bede O, Tiszlavicz L, Onozo B, Virag I, Turi S. Pulmonary capillary haemangiomatosis in children and adolescents: report of a new case and a review of the literature. Eur J Pediatr. 2004;163(12):731-737. [CrossRef] [PubMed]
 
El-Gabaly M, Farver C, Budev M, Mohammed TL. Pulmonary capillary hemangiomatosis imaging findings and literature update. J Comput Assist Tomogr. 2007;31(4):608-610. [CrossRef] [PubMed]
 
Eltorky MA, Headley AS, Winer-Muram H, Garrett HE Jr, Griffin JP. Pulmonary capillary hemangiomatosis: a clinicopathologic review. Ann Thorac Surg. 1994;57(3):772-776. [CrossRef] [PubMed]
 
Faber CN, Yousem SA, Dauber JH, Griffith BP, Hardesty RL, Paradis IL. Pulmonary capillary hemangiomatosis. A report of three cases and a review of the literature. Am Rev Respir Dis. 1989;140(3):808-813. [CrossRef] [PubMed]
 
Bedsole DL, Klemm K, Zorn GL, Wille KM. Pulmonary capillary hemangiomatosis: a consideration in unexplained pulmonary hypertension. Chest. 2005;128(4_MeetingAbstracts):460S-461S. [CrossRef]
 
Assaad AM, Kawut SM, Arcasoy SM, et al. Platelet-derived growth factor is increased in pulmonary capillary hemangiomatosis. Chest. 2007;131(3):850-855. [CrossRef] [PubMed]
 
Ginns LC, Roberts DH, Mark EJ, Brusch JL, Marler JJ. Pulmonary capillary hemangiomatosis with atypical endotheliomatosis: successful antiangiogenic therapy with doxycycline. Chest. 2003;124(5):2017-2022. [CrossRef] [PubMed]
 
Sullivan A, Chmura K, Cool CD, Voelkel N, Chan ED. Pulmonary capillary hemangiomatosis: an immunohistochemical analysis of vascular remodeling in a fatal case. Chest. 2005;128(6_suppl):576S. [CrossRef] [PubMed]
 
Langleben D, Heneghan JM, Batten AP, et al. Familial pulmonary capillary hemangiomatosis resulting in primary pulmonary hypertension. Ann Intern Med. 1988;109(2):106-109. [CrossRef] [PubMed]
 
Wirbelauer J, Hebestreit H, Marx A, Mark EJ, Speer CP. Familial pulmonary capillary hemangiomatosis early in life. Case Rep Pulmonol. 2011;2011:827591.
 
Faiz SA, Zander DS, Patel B. Don’t clean out the garage? Chest. 2005;128(4_MeetingAbstracts):494S-495S. [CrossRef]
 
Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009;25(14):1754-1760. [CrossRef] [PubMed]
 
McKenna A, Hanna M, Banks E, et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010;20(9):1297-1303. [CrossRef] [PubMed]
 
1000 genomes: a deep catalog of human genetic variation. 1000 Genomes website. http://www.1000genomes.org/. Accessed October 3, 2013.
 
National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project (ESP) exome variant server. NHLBI ESP website. http://evs.gs.washington.edu/EVS/. Accessed October 3, 2013.
 
Ma L, Roman-Campos D, Austin ED, et al. A novel channelopathy in pulmonary arterial hypertension. N Engl J Med. 2013;369(4):351-361. [CrossRef] [PubMed]
 
Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54. [CrossRef] [PubMed]
 
Berlanga JJ, Santoyo J, De Haro C. Characterization of a mammalian homolog of the GCN2 eukaryotic initiation factor 2alpha kinase. Eur J Biochem. 1999;265(2):754-762.
 
Wek RC, Staschke KA. How do tumours adapt to nutrient stress? EMBO J. 2010;29(12):1946-1947. [CrossRef] [PubMed]
 
Ye J, Kumanova M, Hart LS, et al. The GCN2-ATF4 pathway is critical for tumour cell survival and proliferation in response to nutrient deprivation. EMBO J. 2010;29(12):2082-2096. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1. Pedigree of family 1. The c.1153dupG mutation and the c.3766C>T mutation segregate with pulmonary capillary hemangiomatosis (PCH) in the index family (family 1). The unaffected mother (I-2) and unaffected daughter (II.3) carried the c.1153dupG mutation, and the unaffected father (I-1) carried the c.3766C>T mutation. (+) denotes wild-type alleles and (-) denotes mutation. →, the proband; ○, unaffected females; ■, affected males; □, unaffected males; /, deceased family members.Grahic Jump Location
Figure Jump LinkFigure 2. PCH of family 1, member II.1, as demonstrated in explanted lung. A, Note the low-power, somewhat nodular, appearance of the areas of increased alveolar thickness (hematoxylin and eosin, original magnification × 40). B, The higher-power image shows that the increased thickness is due to a proliferation of capillaries. Special stains, including elastic stains and the endothelial marker CD31 confirmed this, but are not shown (hematoxylin and eosin, original magnification × 100). C and D, Images are obtained from surgical biopsies of family 1, member II.2 (hematoxylin and eosin, original magnification × 15). C, The thickened septa are less nodular in appearance and, D, somewhat mimic an interstitial pneumonia. Note the thickened pulmonary artery at 12 o’clock (←), a feature typically observed in patients with capillary hemangiomatosis as a manifestation of pulmonary hypertension. See Figure 1 legend for expansion of abbreviation.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 —Clinical and Molecular Characteristics of Four Patients With PCH and EIF2AK4 Mutations

Dlco = diffusion capacity of lung for carbon monoxide; EIF2AK4 = eukaryotic translation initiation factor 2 α kinase 4; na = not available; PA = pulmonary artery pressure; PCH = pulmonary capillary hemangiomatosis; PCWP = pulmonary capillary wedge pressure; WHO = World Health Organization.

References

Wagenvoort CA, Beetstra A, Spijker J. Capillary haemangiomatosis of the lungs. Histopathology. 1978;2(6):401-406. [CrossRef] [PubMed]
 
Bartyik K, Bede O, Tiszlavicz L, Onozo B, Virag I, Turi S. Pulmonary capillary haemangiomatosis in children and adolescents: report of a new case and a review of the literature. Eur J Pediatr. 2004;163(12):731-737. [CrossRef] [PubMed]
 
El-Gabaly M, Farver C, Budev M, Mohammed TL. Pulmonary capillary hemangiomatosis imaging findings and literature update. J Comput Assist Tomogr. 2007;31(4):608-610. [CrossRef] [PubMed]
 
Eltorky MA, Headley AS, Winer-Muram H, Garrett HE Jr, Griffin JP. Pulmonary capillary hemangiomatosis: a clinicopathologic review. Ann Thorac Surg. 1994;57(3):772-776. [CrossRef] [PubMed]
 
Faber CN, Yousem SA, Dauber JH, Griffith BP, Hardesty RL, Paradis IL. Pulmonary capillary hemangiomatosis. A report of three cases and a review of the literature. Am Rev Respir Dis. 1989;140(3):808-813. [CrossRef] [PubMed]
 
Bedsole DL, Klemm K, Zorn GL, Wille KM. Pulmonary capillary hemangiomatosis: a consideration in unexplained pulmonary hypertension. Chest. 2005;128(4_MeetingAbstracts):460S-461S. [CrossRef]
 
Assaad AM, Kawut SM, Arcasoy SM, et al. Platelet-derived growth factor is increased in pulmonary capillary hemangiomatosis. Chest. 2007;131(3):850-855. [CrossRef] [PubMed]
 
Ginns LC, Roberts DH, Mark EJ, Brusch JL, Marler JJ. Pulmonary capillary hemangiomatosis with atypical endotheliomatosis: successful antiangiogenic therapy with doxycycline. Chest. 2003;124(5):2017-2022. [CrossRef] [PubMed]
 
Sullivan A, Chmura K, Cool CD, Voelkel N, Chan ED. Pulmonary capillary hemangiomatosis: an immunohistochemical analysis of vascular remodeling in a fatal case. Chest. 2005;128(6_suppl):576S. [CrossRef] [PubMed]
 
Langleben D, Heneghan JM, Batten AP, et al. Familial pulmonary capillary hemangiomatosis resulting in primary pulmonary hypertension. Ann Intern Med. 1988;109(2):106-109. [CrossRef] [PubMed]
 
Wirbelauer J, Hebestreit H, Marx A, Mark EJ, Speer CP. Familial pulmonary capillary hemangiomatosis early in life. Case Rep Pulmonol. 2011;2011:827591.
 
Faiz SA, Zander DS, Patel B. Don’t clean out the garage? Chest. 2005;128(4_MeetingAbstracts):494S-495S. [CrossRef]
 
Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009;25(14):1754-1760. [CrossRef] [PubMed]
 
McKenna A, Hanna M, Banks E, et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010;20(9):1297-1303. [CrossRef] [PubMed]
 
1000 genomes: a deep catalog of human genetic variation. 1000 Genomes website. http://www.1000genomes.org/. Accessed October 3, 2013.
 
National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project (ESP) exome variant server. NHLBI ESP website. http://evs.gs.washington.edu/EVS/. Accessed October 3, 2013.
 
Ma L, Roman-Campos D, Austin ED, et al. A novel channelopathy in pulmonary arterial hypertension. N Engl J Med. 2013;369(4):351-361. [CrossRef] [PubMed]
 
Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54. [CrossRef] [PubMed]
 
Berlanga JJ, Santoyo J, De Haro C. Characterization of a mammalian homolog of the GCN2 eukaryotic initiation factor 2alpha kinase. Eur J Biochem. 1999;265(2):754-762.
 
Wek RC, Staschke KA. How do tumours adapt to nutrient stress? EMBO J. 2010;29(12):1946-1947. [CrossRef] [PubMed]
 
Ye J, Kumanova M, Hart LS, et al. The GCN2-ATF4 pathway is critical for tumour cell survival and proliferation in response to nutrient deprivation. EMBO J. 2010;29(12):2082-2096. [CrossRef] [PubMed]
 
NOTE:
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