- Email: [email protected]
Linkage Analysis in a Large Family With Primary Pulmonary Hypertension
Linkage Analysis in a Large Family With Primary Pulmonary Hypertension* Genetic Heterogeneity and a Second Primary Pulmonary Hypertension Locus on 2q31–32 Bart Janssen, PhD; Matthias Rindermann; Ulrike Barth, PhD; Gabriel Miltenberger-Miltenyi, MD; Derliz Mereles, MD; Adel Abushi, MD; Werner Seeger, MD; Wolfgang Ku¨ bler, MD; Claus R. Bartram, MD; and Ekkehard Gru¨ nig, MD
(CHEST 2002; 121:54S–56S) Abbreviations: BMPR2 ⫽ bone morphogenetic protein receptor type II; DHPLC ⫽ denaturing high performance liquid chromotography; LOD ⫽ logarithm of the odds for linkage; PASP ⫽ pulmonary artery systolic pressure; PPH ⫽ primary pulmonary hypertension
pulmonary hypertension (PPH) is an autosomal P rimary dominant disorder with an estimated incidence of
about one to two cases per million. The disease is characterized by increased resistance of precapillary pulmonary arteries and leads to sustained elevation of pulmonary arterial pressure (mean pressure ⬎ 25 mm Hg at rest or ⬎ 30 mm Hg during exercise).1 The disease can occur at any stage throughout life from infancy onwards. The mean age at onset is 36 years, and the median length of survival without treatment is ⬍ 3 years after diagnosis.2 Therefore, even in large families, there will never be a high number of living family members with manifest PPH at any one time point. As a consequence, linkage studies are hampered by low numbers of living patients. Despite these problems, American and British investigators managed to find the gene locus and to identify the trait-causing gene: the bone morphogenetic protein receptor type II (BMPR2) gene on chromosome 2q33.3,4 The BMPR2 gene is mutated in a significant proportion of PPH patients, and studies on large cohorts have shown mutation detection rates ranging from 26% in sporadic PPH to 48% in familial cases.5,6 Nevertheless, it appears to be impossible to find all or almost all mutations in a cohort of patients. Several plausible explanations for this problem can be mentioned, like a mutational hot spot in a regulatory element or undetected locus heterogeneity. So far, it was not possible to investigate the latter explanation due to the limited number of living patients. Our echocardiographic studies have demonstrated that a predisposition to PPH can be diagnosed at an early stage *From the Institute of Human Genetics (Drs. Janssen, Barth, Miltenberger-Miltenyi, and Bartram and Mr. Rindermann), University of Heidelberg, Heidelberg; Department of Cardiology (Drs. Mereles, Abushi, Ku¨ bler, and Gru¨ nig), University of Heidelberg, Heidelberg; and Department of Pneumonology (Dr. Seeger), University of Giessen, Giessen, Germany. Correspondence to: Bart Janssen, PhD, Institute of Human Genetics, Im Neuenheimer Feld 328, 69120 Heidelberg, Germany; e-mail: [email protected] 54S
of disease using stress Doppler echocardiography.7 A pathologic rise of pulmonary artery systolic pressure (PASP) during supine bicycle exercise (⬎ 40 mm Hg) was observed only in those family members who shared the risk haplotype with the index patients. To investigate the genetic cause in BMPR2-negative PPH patients, we analyzed a large family with PPH and a normal BMPR2 gene using linkage analysis, stress Doppler echocardiography and, in some family members, right-heart catheterization.
Methods and Results We studied a large German pedigree with four generations (Fig 1). The family has been described previously by Gru¨ nig et al.7 Individuals were classified as carriers if they had a diagnosis of manifest PPH (pulmonary artery pressure ⬎ 25 mm Hg, or PASP ⬎ 35 mm Hg at rest, after excluding secondary PPH), or if stress Doppler echocardiography revealed a pathologic increase of PASP (ⱖ 45 mm Hg) during supine bicycle exercise. Family members with a maximum PASP of ⱕ 35 mm Hg were classified as normal. All family members with intermediate PASP values (⬎ 35 mm Hg and ⬍ 45 mm Hg) and family members suspected as having pulmonary hypertension due to secondary causes were classified as status unknown. The intermediate PASP range corresponds to the SD at high heart rates and was introduced to avoid the occurrence of false recombinations. In total, we studied 57 family members. A manifest PPH was diagnosed in two family members. A PPH carrier status was found by Doppler echocardiography in 12 individuals; in another 12 family members, the PASP values were normal. The remaining family members had secondary pulmonary hypertension, were not available for clinical investigation, revealed inadequate Doppler echocardiographic signals, or revealed intermediate PASP values and were therefore classified as status unknown. All adult cases with manifest PPH or a PPH carrier status were reinvestigated by right-heart catheterization. In each case, the stress echocardiographic data were confirmed. BMPR2 mutations were excluded by DHPLC analysis. The family was genotyped for the markers shown in Figure 1, location scores (logarithm of the odds for linkage [LOD] scores, Z) were computed at 1-centimorgan intervals, and haplotypes were constructed manually. The multipoint analysis showed high LOD scores in the proximal part of the PPH candidate region, whereas insignificant LOD scores (Z ⬍ 0.1) were obtained for the more distal markers linked to BMPR2 (locus PPH1). The haplotypes indicated that recombinations with the PPH1 locus occurred in one unaffected family member (V-7) and in two members who showed a pathologic increase of PASP (51 mm Hg and 47 mm Hg, respectively) during supine bicycle exercise (IV-2 and IV-7) [Fig 1]. The maximum LOD score for this family was found at the position of marker D2S2307 (Z maximum, 4.54). At the BMPR2-linked marker D2S307, the LOD score was 0.07. A PASP of 40 mm Hg during supine bicycle exercise is generally accepted as maximal for normal individuals.8,9 Based on these findings, we had to consider the individuals with pathologic PASP as genuine PPH carriers, despite the recombinant haplotypes.
Thomas L. Petty 44th Annual Aspen Lung Conference: Pulmonary Genetics, Genomics, Gene Therapy
Figure 1. Haplotypes for PPH family 965. Filled symbols indicate manifest PPH. Half-filled symbols indicate abnormal PASP response to exercise (⬎ 45 mm Hg). The risk haplotypes are drawn black. This figure clearly illustrates the significant gain of genetic information obtained using stress Doppler echocardiography for the identification of gene carriers (individuals with an abnormal PASP response). In order to minimize the number of diagnostic errors, we excluded individuals with PASP values between 35 mm Hg and 45 mm Hg. As a result of this exclusion, we scored fewer cases of nonpenetrance compared to our previous study.7 The only apparent case of nonpenetrance is individual V-8. This girl was 10 years old when she was tested and showed a maximum PASP of 30 mm Hg during exercise and 25 mm Hg at rest. The marker order is D2S335, D2S2307, D2S2188, D2S2981, D2S2314, D2S350, D2S309, D2S307, and D2S360. The BMPR2 gene maps in-between D2S309 and D2S307. Linkage to the BMPR2 locus is questionable. On the contrary, linkage to the more proximal locus D2S2307 is supported by a significant LOD score (Z ⫽ 4.54).
Conclusion The results of our study suggest linkage heterogeneity in PPH with a second locus, designated PPH2, located on chromosome 2q31–32. According to the haplotypes, the PPH2 locus maps in between the markers D2S335 and D2S2314 (Fig 1). Since PPH1 (BMPR2) and PPH2 lie only 15 to 19 centimorgans apart, many small families will show no recombination between the two regions. Therefore, it is not possible to classify small families by means of haplotype analysis. This might explain why several authors failed to find BMPR2 mutations in several families that showed marker data consistent with linkage to 2q33. The genetic classification of our families would not have been possible without the novel diagnostic procedure involving stress Doppler echocardiography. Although we studied a PPH-related phenotype rather
than PPH itself, the haplotype information demonstrates that the PPH2 locus is not the site of a modifier gene, modifying the PPH phenotype toward a trait detectable by stress Doppler echocardiography, but the site of a mutation that is the direct cause of PPH. We conclude that stress Doppler echocardiography enables the investigators to identify carriers of the disease, nearly independent of the state of the disease process. Although the use of an intermediate range ensures that we only counted genuine recombinations, we noticed that 15 noncarriers and only 2 carriers were excluded from the study due to intermediate PASP values. Therefore, the use of an intermediate range and the exact cutoff value needs further evaluation. Our data indicate that a second PPH gene maps to 2q31–32. This map position is supported by a highly significant LOD score. We realize that more conclusive CHEST / 121 / 3 / MARCH, 2002 SUPPLEMENT
55S
evidence should come from studies on larger numbers of families. Such a study is currently in progress in our institutions.
References 1 Rubin L. ACCP consensus statement: primary pulmonary hypertension. Chest 1993; 104:236 –250 2 D’Allonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension: results from a national prospective registry. Ann Intern Med 1991; 115:343–349 3 Deng Z, Morse JH, Slager SL, et al. Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet 2000; 67:737–744 4 The International PPH Consortium. Heterozygous germline mutations in BMPR2, encoding a TGF- receptor, cause familial primary pulmonary hypertension. Nat Genet 2000; 26:81– 84 5 Thomson JR, Machado RD, Pauciulo MW, et al. Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF- family. J Med Genet 2000; 37:741–745 6 Massague´ J, Chen Y. Controlling TGF- signaling. Genes Dev 2000; 14:627– 644 7 Gru¨ nig E, Janssen B, Mereles D, et al. Abnormal pulmonary artery pressure response in asymptomatic carriers of primary pulmonary hypertension gene. Circulation 2000; 102:1145– 1150 8 Gurtner HP, Walser P, Fa¨ ssler B. Normal values for pulmonary hemodynamics at rest and during exercise in man. Prog Respir Res 1995; 9:295–315 9 Janosi A, Apor P, Hankoczy J, et al. Pulmonary artery pressure and oxygen consumption measurement during supine bicycle exercise. Chest 1998; 93:419 – 421
Genetics and Gene Expression in Lymphangioleiomyomatosis*
Key words: lymphangioleiomyomatosis; tuberous sclerosis complex Abbreviations: Dlco ⫽ diffusing capacity of the lung for carbon monoxide; HRCT ⫽ high-resolution CT; HUMAR ⫽ human androgen receptor; LAM ⫽ lymphangioleiomyomatosis; LOH ⫽ loss of heterozygosity; MMPH ⫽ multifocal micronodular pneumocyte hyperplasia; PCR ⫽ polymerase chain reaction; TSC ⫽ tuberous sclerosis complex
(LAM), a rare disease that L ymphangioleiomyomatosis is characterized by cystic destruction of the lung leading to chronic respiratory failure, is found primarily in women of childbearing age. It is a multisystem disorder and is also associated with abdominal tumors (eg, angiomyolipomas, lymphangioleiomyomas). The lung cysts and abdominal tumors are characterized by the presence of abnormal smooth muscle cells (ie, LAM cells). Epidemiologic, genetic, and molecular studies have demonstrated a link between sporadic LAM and tuberous sclerosis complex (TSC), an autosomal-dominant neurocutaneous disorder with variable penetrance caused by mutations in the TSC1 and TSC2 genes. Here, we discuss the clinical characteristics of LAM, the association of LAM and TSC, the morphologic characteristics of abnormal smooth muscle proliferative lesions, as well as gene and protein abnormalities that are characteristic of both sporadic LAM and LAM in patients with TSC.
Clinical Characteristics
Giles F. Filley Lecture Gustavo Pacheco-Rodriguez, PhD; Arnold S. Kristof, MD; Linda A. Stevens; Yi Zhang, PhD; Denise Crooks, PhD; and Joel Moss, MD, PhD
Lymphangioleiomyomatosis (LAM) is a disease of unknown etiology that is characterized by the proliferation of abnormal smooth muscle cells (LAM cells) in the lung, which leads to cystic parenchymal destruction and progressive respiratory failure. Recent evidence suggests that the proliferative and invasive *From the Pulmonary-Critical Care Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD. Correspondence to: Joel Moss, MD, PhD, Chief, PulmonaryCritical Care Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, 10 Center Dr, Bldg 10, Room 6 D05, MSC 1590, Bethesda, MD 20892-1590; e-mail: [email protected] 56S
nature of LAM cells may be due, in part, to somatic mutations in the TSC2 gene, which has been implicated in the pathogenesis of tuberous sclerosis complex. Here, we describe the clinical and molecular characteristics of LAM, as well as the efforts now under way to understand the genetic and biochemical factors that lead to progressive pulmonary destruction and, ultimately, to lung transplantation or death. (CHEST 2002; 121:56S– 60S)
LAM is characterized by progressive respiratory failure and recurrent pneumothoraces.1 The clinical characteristics of LAM were investigated in three detailed studies.1–3 Patients presented with dyspnea due to small airway obstruction and/or chylous pleural effusion, chronic cough, or acute chest pain resulting from pneumothorax. Wheezing and hemoptysis occured less commonly, with 26% of patients having evidence of airway hyperreactivity. Asymptomatic lung disease may be discovered after the diagnosis of abdominal angiomyolipomas or axial lymphatic masses.4 Symptoms arising from abdominal lesions include flank pain, hematuria, and abdominal distension. Retroperitoneal lymphatic involvement can give rise to significant lymphedema and neuropathies. Physical examination of the lungs most commonly reveals crackles and decreased breath sounds, which are consistent with parenchymal destruction or chylous effusion. Wheezing is heard in 14% of patients, and clubbing is a rare finding. Cardiac examination may provide evi-
Thomas L. Petty 44th Annual Aspen Lung Conference: Pulmonary Genetics, Genomics, Gene Therapy
(CHEST 2002; 121:54S–56S) Abbreviations: BMPR2 ⫽ bone morphogenetic protein receptor type II; DHPLC ⫽ denaturing high performance liquid chromotography; LOD ⫽ logarithm of the odds for linkage; PASP ⫽ pulmonary artery systolic pressure; PPH ⫽ primary pulmonary hypertension
pulmonary hypertension (PPH) is an autosomal P rimary dominant disorder with an estimated incidence of
about one to two cases per million. The disease is characterized by increased resistance of precapillary pulmonary arteries and leads to sustained elevation of pulmonary arterial pressure (mean pressure ⬎ 25 mm Hg at rest or ⬎ 30 mm Hg during exercise).1 The disease can occur at any stage throughout life from infancy onwards. The mean age at onset is 36 years, and the median length of survival without treatment is ⬍ 3 years after diagnosis.2 Therefore, even in large families, there will never be a high number of living family members with manifest PPH at any one time point. As a consequence, linkage studies are hampered by low numbers of living patients. Despite these problems, American and British investigators managed to find the gene locus and to identify the trait-causing gene: the bone morphogenetic protein receptor type II (BMPR2) gene on chromosome 2q33.3,4 The BMPR2 gene is mutated in a significant proportion of PPH patients, and studies on large cohorts have shown mutation detection rates ranging from 26% in sporadic PPH to 48% in familial cases.5,6 Nevertheless, it appears to be impossible to find all or almost all mutations in a cohort of patients. Several plausible explanations for this problem can be mentioned, like a mutational hot spot in a regulatory element or undetected locus heterogeneity. So far, it was not possible to investigate the latter explanation due to the limited number of living patients. Our echocardiographic studies have demonstrated that a predisposition to PPH can be diagnosed at an early stage *From the Institute of Human Genetics (Drs. Janssen, Barth, Miltenberger-Miltenyi, and Bartram and Mr. Rindermann), University of Heidelberg, Heidelberg; Department of Cardiology (Drs. Mereles, Abushi, Ku¨ bler, and Gru¨ nig), University of Heidelberg, Heidelberg; and Department of Pneumonology (Dr. Seeger), University of Giessen, Giessen, Germany. Correspondence to: Bart Janssen, PhD, Institute of Human Genetics, Im Neuenheimer Feld 328, 69120 Heidelberg, Germany; e-mail: [email protected] 54S
of disease using stress Doppler echocardiography.7 A pathologic rise of pulmonary artery systolic pressure (PASP) during supine bicycle exercise (⬎ 40 mm Hg) was observed only in those family members who shared the risk haplotype with the index patients. To investigate the genetic cause in BMPR2-negative PPH patients, we analyzed a large family with PPH and a normal BMPR2 gene using linkage analysis, stress Doppler echocardiography and, in some family members, right-heart catheterization.
Methods and Results We studied a large German pedigree with four generations (Fig 1). The family has been described previously by Gru¨ nig et al.7 Individuals were classified as carriers if they had a diagnosis of manifest PPH (pulmonary artery pressure ⬎ 25 mm Hg, or PASP ⬎ 35 mm Hg at rest, after excluding secondary PPH), or if stress Doppler echocardiography revealed a pathologic increase of PASP (ⱖ 45 mm Hg) during supine bicycle exercise. Family members with a maximum PASP of ⱕ 35 mm Hg were classified as normal. All family members with intermediate PASP values (⬎ 35 mm Hg and ⬍ 45 mm Hg) and family members suspected as having pulmonary hypertension due to secondary causes were classified as status unknown. The intermediate PASP range corresponds to the SD at high heart rates and was introduced to avoid the occurrence of false recombinations. In total, we studied 57 family members. A manifest PPH was diagnosed in two family members. A PPH carrier status was found by Doppler echocardiography in 12 individuals; in another 12 family members, the PASP values were normal. The remaining family members had secondary pulmonary hypertension, were not available for clinical investigation, revealed inadequate Doppler echocardiographic signals, or revealed intermediate PASP values and were therefore classified as status unknown. All adult cases with manifest PPH or a PPH carrier status were reinvestigated by right-heart catheterization. In each case, the stress echocardiographic data were confirmed. BMPR2 mutations were excluded by DHPLC analysis. The family was genotyped for the markers shown in Figure 1, location scores (logarithm of the odds for linkage [LOD] scores, Z) were computed at 1-centimorgan intervals, and haplotypes were constructed manually. The multipoint analysis showed high LOD scores in the proximal part of the PPH candidate region, whereas insignificant LOD scores (Z ⬍ 0.1) were obtained for the more distal markers linked to BMPR2 (locus PPH1). The haplotypes indicated that recombinations with the PPH1 locus occurred in one unaffected family member (V-7) and in two members who showed a pathologic increase of PASP (51 mm Hg and 47 mm Hg, respectively) during supine bicycle exercise (IV-2 and IV-7) [Fig 1]. The maximum LOD score for this family was found at the position of marker D2S2307 (Z maximum, 4.54). At the BMPR2-linked marker D2S307, the LOD score was 0.07. A PASP of 40 mm Hg during supine bicycle exercise is generally accepted as maximal for normal individuals.8,9 Based on these findings, we had to consider the individuals with pathologic PASP as genuine PPH carriers, despite the recombinant haplotypes.
Thomas L. Petty 44th Annual Aspen Lung Conference: Pulmonary Genetics, Genomics, Gene Therapy
Figure 1. Haplotypes for PPH family 965. Filled symbols indicate manifest PPH. Half-filled symbols indicate abnormal PASP response to exercise (⬎ 45 mm Hg). The risk haplotypes are drawn black. This figure clearly illustrates the significant gain of genetic information obtained using stress Doppler echocardiography for the identification of gene carriers (individuals with an abnormal PASP response). In order to minimize the number of diagnostic errors, we excluded individuals with PASP values between 35 mm Hg and 45 mm Hg. As a result of this exclusion, we scored fewer cases of nonpenetrance compared to our previous study.7 The only apparent case of nonpenetrance is individual V-8. This girl was 10 years old when she was tested and showed a maximum PASP of 30 mm Hg during exercise and 25 mm Hg at rest. The marker order is D2S335, D2S2307, D2S2188, D2S2981, D2S2314, D2S350, D2S309, D2S307, and D2S360. The BMPR2 gene maps in-between D2S309 and D2S307. Linkage to the BMPR2 locus is questionable. On the contrary, linkage to the more proximal locus D2S2307 is supported by a significant LOD score (Z ⫽ 4.54).
Conclusion The results of our study suggest linkage heterogeneity in PPH with a second locus, designated PPH2, located on chromosome 2q31–32. According to the haplotypes, the PPH2 locus maps in between the markers D2S335 and D2S2314 (Fig 1). Since PPH1 (BMPR2) and PPH2 lie only 15 to 19 centimorgans apart, many small families will show no recombination between the two regions. Therefore, it is not possible to classify small families by means of haplotype analysis. This might explain why several authors failed to find BMPR2 mutations in several families that showed marker data consistent with linkage to 2q33. The genetic classification of our families would not have been possible without the novel diagnostic procedure involving stress Doppler echocardiography. Although we studied a PPH-related phenotype rather
than PPH itself, the haplotype information demonstrates that the PPH2 locus is not the site of a modifier gene, modifying the PPH phenotype toward a trait detectable by stress Doppler echocardiography, but the site of a mutation that is the direct cause of PPH. We conclude that stress Doppler echocardiography enables the investigators to identify carriers of the disease, nearly independent of the state of the disease process. Although the use of an intermediate range ensures that we only counted genuine recombinations, we noticed that 15 noncarriers and only 2 carriers were excluded from the study due to intermediate PASP values. Therefore, the use of an intermediate range and the exact cutoff value needs further evaluation. Our data indicate that a second PPH gene maps to 2q31–32. This map position is supported by a highly significant LOD score. We realize that more conclusive CHEST / 121 / 3 / MARCH, 2002 SUPPLEMENT
55S
evidence should come from studies on larger numbers of families. Such a study is currently in progress in our institutions.
References 1 Rubin L. ACCP consensus statement: primary pulmonary hypertension. Chest 1993; 104:236 –250 2 D’Allonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension: results from a national prospective registry. Ann Intern Med 1991; 115:343–349 3 Deng Z, Morse JH, Slager SL, et al. Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet 2000; 67:737–744 4 The International PPH Consortium. Heterozygous germline mutations in BMPR2, encoding a TGF- receptor, cause familial primary pulmonary hypertension. Nat Genet 2000; 26:81– 84 5 Thomson JR, Machado RD, Pauciulo MW, et al. Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF- family. J Med Genet 2000; 37:741–745 6 Massague´ J, Chen Y. Controlling TGF- signaling. Genes Dev 2000; 14:627– 644 7 Gru¨ nig E, Janssen B, Mereles D, et al. Abnormal pulmonary artery pressure response in asymptomatic carriers of primary pulmonary hypertension gene. Circulation 2000; 102:1145– 1150 8 Gurtner HP, Walser P, Fa¨ ssler B. Normal values for pulmonary hemodynamics at rest and during exercise in man. Prog Respir Res 1995; 9:295–315 9 Janosi A, Apor P, Hankoczy J, et al. Pulmonary artery pressure and oxygen consumption measurement during supine bicycle exercise. Chest 1998; 93:419 – 421
Genetics and Gene Expression in Lymphangioleiomyomatosis*
Key words: lymphangioleiomyomatosis; tuberous sclerosis complex Abbreviations: Dlco ⫽ diffusing capacity of the lung for carbon monoxide; HRCT ⫽ high-resolution CT; HUMAR ⫽ human androgen receptor; LAM ⫽ lymphangioleiomyomatosis; LOH ⫽ loss of heterozygosity; MMPH ⫽ multifocal micronodular pneumocyte hyperplasia; PCR ⫽ polymerase chain reaction; TSC ⫽ tuberous sclerosis complex
(LAM), a rare disease that L ymphangioleiomyomatosis is characterized by cystic destruction of the lung leading to chronic respiratory failure, is found primarily in women of childbearing age. It is a multisystem disorder and is also associated with abdominal tumors (eg, angiomyolipomas, lymphangioleiomyomas). The lung cysts and abdominal tumors are characterized by the presence of abnormal smooth muscle cells (ie, LAM cells). Epidemiologic, genetic, and molecular studies have demonstrated a link between sporadic LAM and tuberous sclerosis complex (TSC), an autosomal-dominant neurocutaneous disorder with variable penetrance caused by mutations in the TSC1 and TSC2 genes. Here, we discuss the clinical characteristics of LAM, the association of LAM and TSC, the morphologic characteristics of abnormal smooth muscle proliferative lesions, as well as gene and protein abnormalities that are characteristic of both sporadic LAM and LAM in patients with TSC.
Clinical Characteristics
Giles F. Filley Lecture Gustavo Pacheco-Rodriguez, PhD; Arnold S. Kristof, MD; Linda A. Stevens; Yi Zhang, PhD; Denise Crooks, PhD; and Joel Moss, MD, PhD
Lymphangioleiomyomatosis (LAM) is a disease of unknown etiology that is characterized by the proliferation of abnormal smooth muscle cells (LAM cells) in the lung, which leads to cystic parenchymal destruction and progressive respiratory failure. Recent evidence suggests that the proliferative and invasive *From the Pulmonary-Critical Care Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD. Correspondence to: Joel Moss, MD, PhD, Chief, PulmonaryCritical Care Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, 10 Center Dr, Bldg 10, Room 6 D05, MSC 1590, Bethesda, MD 20892-1590; e-mail: [email protected] 56S
nature of LAM cells may be due, in part, to somatic mutations in the TSC2 gene, which has been implicated in the pathogenesis of tuberous sclerosis complex. Here, we describe the clinical and molecular characteristics of LAM, as well as the efforts now under way to understand the genetic and biochemical factors that lead to progressive pulmonary destruction and, ultimately, to lung transplantation or death. (CHEST 2002; 121:56S– 60S)
LAM is characterized by progressive respiratory failure and recurrent pneumothoraces.1 The clinical characteristics of LAM were investigated in three detailed studies.1–3 Patients presented with dyspnea due to small airway obstruction and/or chylous pleural effusion, chronic cough, or acute chest pain resulting from pneumothorax. Wheezing and hemoptysis occured less commonly, with 26% of patients having evidence of airway hyperreactivity. Asymptomatic lung disease may be discovered after the diagnosis of abdominal angiomyolipomas or axial lymphatic masses.4 Symptoms arising from abdominal lesions include flank pain, hematuria, and abdominal distension. Retroperitoneal lymphatic involvement can give rise to significant lymphedema and neuropathies. Physical examination of the lungs most commonly reveals crackles and decreased breath sounds, which are consistent with parenchymal destruction or chylous effusion. Wheezing is heard in 14% of patients, and clubbing is a rare finding. Cardiac examination may provide evi-
Thomas L. Petty 44th Annual Aspen Lung Conference: Pulmonary Genetics, Genomics, Gene Therapy