Mutation of Perinatal Myosin Heavy Chain
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《新英格兰医药杂志》
To the Editor: Veugelers et al. (July 29 issue)1 report on patients with the trismus–pseudocamptodactyly syndrome as having a "Carney complex variant." Among more than 500 patients with the Carney complex in our database, there are none with the trismus–pseudocamptodactyly syndrome.2,3
In our analysis of patients reported to have the trismus–pseudocamptodactyly syndrome, we identified several with freckling. These patients appeared to have a familial disorder at variance with the Carney complex — not a simple Carney complex variant. The dictionary definition of variant is "varying usually slightly from the standard form." By contrast, patients with the trismus–pseudo-camptodactyly syndrome have none of the lesions or endocrine syndromes that are typical of the Carney complex.2 The confusion caused by the suggested terminology is apparent in the Perspective article that accompanies the report by Veugelers et al.: in that article, the table listing the disorders caused by abnormal myosins refers to "Carney complex (trismus–pseudocamptodactyly)," without the qualifier "variant."4 The trismus–pseudocamptodactyly syndrome with freckling may or may not be associated with familial myxomas and may or may not be caused by a single mutation of the MYH8 gene, but our data indicate that this disorder is distinct from the Carney complex.
Constantine A. Stratakis, M.D., D.Sci.
National Institutes of Health
Bethesda, MD 20892
stratakc@mail.nih.gov
Jerome Bertherat, M.D.
H?pital Cochin
75014 Paris, France
J. Aidan Carney, M.D., Ph.D.
Mayo Clinic
Rochester, MN 55905
References
Veugelers M, Bressan M, McDermott DA, et al. Mutation of perinatal myosin heavy chain associated with a Carney complex variant. N Engl J Med 2004;351:460-469.
Stratakis CA, Kirschner LS, Carney JA. Clinical and molecular features of the Carney complex: diagnostic criteria and recommendations for patient evaluation. J Clin Endocrinol Metab 2001;86:4041-4046.
Groussin L, Kirschner LS, Vincent-Dejean C, et al. Molecular analysis of the cyclic AMP-dependent protein kinase A (PKA) regulatory subunit 1A (PRKAR1A) gene in patients with Carney complex and primary pigmented nodular adrenocortical disease (PPNAD) reveals novel mutations and clues for pathophysiology: augmented PKA signaling is associated with adrenal tumorigenesis in PPNAD. Am J Hum Genet 2002;71:1433-1442.
Tardiff JC. Myosin at the heart of the problem. N Engl J Med 2004;351:424-426.
To the Editor: In the report by Veugelers and colleagues on mutations in the MYH8 gene as a cause of the Carney complex (the trismus–pseudocamptodactyly syndrome), the authors report screening the gene for variants that may be associated with isolated cardiac myxoma. In 12 presumably unrelated patients screened for the polymorphism T5147C, 4 T/T homozygotes and 8 C/C homozygotes were identified. These findings are not in Hardy–Weinberg equilibrium (P<0.001), owing to the presence of fewer than the expected number of heterozygotes. Possible explanations for these findings are that the 12 cases are actually closely related, that there was a genotyping or typographic error, or that a true disease association was observed, one most likely involving one or more unidentified deletions. Could it be that this finding does implicate MYH8 in "sporadic" cardiac myxoma?
Matthew A. Brown, M.B., B.S.
University of Oxford
Oxford OX3 7LD, United Kingdom
mbrown@well.ox.ac.uk
To the Editor: Veugelers et al. clearly demonstrate the novel gene mutation that is a cause of the Carney complex variant. We would appreciate it if they could provide additional data on two issues. First, are there any data on the morphologic or electrophysiological abnormality of myocardium in Family 1? A report indicating that MYH8 is expressed in the embryonic myocardium in the chick1 suggests that a mutation of MYH8 may impede early cardiogenesis in humans. The influence of this genetic defect on cardiogenesis should be studied, as well as cardiac tumorigenesis. Such a discussion would provide insight into the role of the perinatal myosin heavy chain in cardiogenesis. Second, the polymorphism (M1229T) of MYH8 that the authors identify as a possible risk factor for cardiac myxomas may function as a genetic modifier,2 which may in part explain the difference in phenotypic expressivity between Family 1 and Families 2 and 3. This analysis would provide a good example of genetic modifiers within a single gene.
Hiroyuki Morita, M.D., Ph.D.
Ryozo Nagai, M.D., Ph.D.
University of Tokyo
Tokyo 113-8655, Japan
hmrt-tky@umin.ac.jp
References
Machida S, Matsuoka R, Noda S, et al. Evidence for the expression of neonatal skeletal myosin heavy chain in primary myocardium and cardiac conduction tissue in the developing chick heart. Dev Dyn 2000;217:37-49.
Dipple KM, McCabe ER. Phenotypes of patients with "simple" Mendelian disorders are complex traits: thresholds, modifiers, and systems dynamics. Am J Hum Genet 2000;66:1729-1735.
The authors reply: Dr. Brown and Drs. Morita and Nagai emphasize the potential contributions of MYH8 polymorphisms to cardiac myxomas. We, too, observed the deviation from Hardy–Weinberg equilibrium in our cohort of 12 patients with cardiac myxomas,1 none of whom are apparently related. To date, we have not found evidence of deletions to confound the genotyping (flanking polymorphisms show heterozygosity), but we agree that the possibility of microdeletions cannot be excluded. Such comments highlight the need for further study of genotype–phenotype correlations in larger cohorts and of the possible clinical effect of MYH8 variants on the risk of cardiac tumorigenesis.
Drs. Morita and Nagai also ask intriguing questions about the potential role of MYH8 in the development of the heart. Echocardiography and electrocardiography have not yet revealed congenital malformations in Family 1, 2, or 3. However, more detailed analyses are ongoing, and we concur with regard to the importance of direct experimentation to determine the contributions of MYH8 to cardiogenesis. We note that, in conformance to the policy of the Journal, the numbering of the families described in our report was changed from that used in previous reports,2 so that correlating the clinical findings in our report with those in the earlier reports can be confusing. The ventriculogram from family member II-7 (Family 1, or YK) in Figure 1C of the article1 shows a similar image from a frame cut from cine film of the same cardiac myxoma shown in an earlier description of this proband.2 Chaudron et al.2 showed an image of the face of family member II-7 that bears a striking similarity to the photograph in our report (Figure 1B1) of her daughter (III-19), who also has the Carney complex and the trismus–pseudocamptodactyly syndrome.
Stratakis and colleagues misread our study. Although the use of precise terminology is important, we did not suggest that all patients with the trismus–pseudocamptodactyly syndrome have a Carney complex variant. Rather, we reported that some unusual patients with typical Carney complex findings also have the trismus–pseudocamptodactyly syndrome, and we termed these combined disorders a Carney complex variant. The typical Carney complex exhibits markedly variable expressivity,3,4,5 and the only feature that occurs nearly uniformly is spotty pigmentation. Among the myriad other findings that occasionally occur, some of the more frequent ones are cardiac, cutaneous, and palpebral myxomas as well as endocrine syndromes such as acromegaly. All these cardiac, dermatologic, neoplastic, and endocrine manifestations were seen and reported in the family described with the variant Carney complex.1,2 We encourage caution when analyzing data from previously established Carney complex databases to identify persons with this rare variant. Such a retrospective review is likely to be insensitive, because the diagnosis of pseudocamptodactyly (in contrast to camptodactyly) requires a focused evaluation of the patient with particular physical examination maneuvers. Identification of the trismus–pseudocamptodactyly syndrome in these cohorts with the Carney complex requires that specifically trained physicians reevaluate them prospectively.
Craig T. Basson, M.D., Ph.D.
Mark Veugelers, Ph.D.
Deborah A. McDermott, M.S.
Weill Medical College of Cornell University
New York, NY 10021
ctbasson@med.cornell.edu
References
Veugelers M, Bressan M, McDermott DA, et al. Mutation of perinatal myosin heavy chain associated with a Carney complex variant. N Engl J Med 2004;351:460-469.
Chaudron JM, Jacques JM, Heller FR, Cheron P, Luwaert R. The myxoma syndrome: an unusual entity: a family study. Eur Heart J 1992;13:569-573.
Stratakis CA, Carney JA, Lin JP, et al. Carney complex, a familial multiple neoplasia and lentiginosis syndrome: analysis of 11 kindreds and linkage to the short arm of chromosome 2. J Clin Invest 1996;97:699-705.
Casey M, Mah C, Merliss AD, et al. Identification of a novel genetic locus for familial cardiac myxomas and Carney complex. Circulation 1998;98:2560-2566.
Veugelers M, Wilkes D, Burton KA, et al. Comparative PRKAR1A genotype-phenotype analyses in humans with Carney complex and prkar1a haploinsufficient mice. Proc Natl Acad Sci U S A 2004;101:14222-14227.
In our analysis of patients reported to have the trismus–pseudocamptodactyly syndrome, we identified several with freckling. These patients appeared to have a familial disorder at variance with the Carney complex — not a simple Carney complex variant. The dictionary definition of variant is "varying usually slightly from the standard form." By contrast, patients with the trismus–pseudo-camptodactyly syndrome have none of the lesions or endocrine syndromes that are typical of the Carney complex.2 The confusion caused by the suggested terminology is apparent in the Perspective article that accompanies the report by Veugelers et al.: in that article, the table listing the disorders caused by abnormal myosins refers to "Carney complex (trismus–pseudocamptodactyly)," without the qualifier "variant."4 The trismus–pseudocamptodactyly syndrome with freckling may or may not be associated with familial myxomas and may or may not be caused by a single mutation of the MYH8 gene, but our data indicate that this disorder is distinct from the Carney complex.
Constantine A. Stratakis, M.D., D.Sci.
National Institutes of Health
Bethesda, MD 20892
stratakc@mail.nih.gov
Jerome Bertherat, M.D.
H?pital Cochin
75014 Paris, France
J. Aidan Carney, M.D., Ph.D.
Mayo Clinic
Rochester, MN 55905
References
Veugelers M, Bressan M, McDermott DA, et al. Mutation of perinatal myosin heavy chain associated with a Carney complex variant. N Engl J Med 2004;351:460-469.
Stratakis CA, Kirschner LS, Carney JA. Clinical and molecular features of the Carney complex: diagnostic criteria and recommendations for patient evaluation. J Clin Endocrinol Metab 2001;86:4041-4046.
Groussin L, Kirschner LS, Vincent-Dejean C, et al. Molecular analysis of the cyclic AMP-dependent protein kinase A (PKA) regulatory subunit 1A (PRKAR1A) gene in patients with Carney complex and primary pigmented nodular adrenocortical disease (PPNAD) reveals novel mutations and clues for pathophysiology: augmented PKA signaling is associated with adrenal tumorigenesis in PPNAD. Am J Hum Genet 2002;71:1433-1442.
Tardiff JC. Myosin at the heart of the problem. N Engl J Med 2004;351:424-426.
To the Editor: In the report by Veugelers and colleagues on mutations in the MYH8 gene as a cause of the Carney complex (the trismus–pseudocamptodactyly syndrome), the authors report screening the gene for variants that may be associated with isolated cardiac myxoma. In 12 presumably unrelated patients screened for the polymorphism T5147C, 4 T/T homozygotes and 8 C/C homozygotes were identified. These findings are not in Hardy–Weinberg equilibrium (P<0.001), owing to the presence of fewer than the expected number of heterozygotes. Possible explanations for these findings are that the 12 cases are actually closely related, that there was a genotyping or typographic error, or that a true disease association was observed, one most likely involving one or more unidentified deletions. Could it be that this finding does implicate MYH8 in "sporadic" cardiac myxoma?
Matthew A. Brown, M.B., B.S.
University of Oxford
Oxford OX3 7LD, United Kingdom
mbrown@well.ox.ac.uk
To the Editor: Veugelers et al. clearly demonstrate the novel gene mutation that is a cause of the Carney complex variant. We would appreciate it if they could provide additional data on two issues. First, are there any data on the morphologic or electrophysiological abnormality of myocardium in Family 1? A report indicating that MYH8 is expressed in the embryonic myocardium in the chick1 suggests that a mutation of MYH8 may impede early cardiogenesis in humans. The influence of this genetic defect on cardiogenesis should be studied, as well as cardiac tumorigenesis. Such a discussion would provide insight into the role of the perinatal myosin heavy chain in cardiogenesis. Second, the polymorphism (M1229T) of MYH8 that the authors identify as a possible risk factor for cardiac myxomas may function as a genetic modifier,2 which may in part explain the difference in phenotypic expressivity between Family 1 and Families 2 and 3. This analysis would provide a good example of genetic modifiers within a single gene.
Hiroyuki Morita, M.D., Ph.D.
Ryozo Nagai, M.D., Ph.D.
University of Tokyo
Tokyo 113-8655, Japan
hmrt-tky@umin.ac.jp
References
Machida S, Matsuoka R, Noda S, et al. Evidence for the expression of neonatal skeletal myosin heavy chain in primary myocardium and cardiac conduction tissue in the developing chick heart. Dev Dyn 2000;217:37-49.
Dipple KM, McCabe ER. Phenotypes of patients with "simple" Mendelian disorders are complex traits: thresholds, modifiers, and systems dynamics. Am J Hum Genet 2000;66:1729-1735.
The authors reply: Dr. Brown and Drs. Morita and Nagai emphasize the potential contributions of MYH8 polymorphisms to cardiac myxomas. We, too, observed the deviation from Hardy–Weinberg equilibrium in our cohort of 12 patients with cardiac myxomas,1 none of whom are apparently related. To date, we have not found evidence of deletions to confound the genotyping (flanking polymorphisms show heterozygosity), but we agree that the possibility of microdeletions cannot be excluded. Such comments highlight the need for further study of genotype–phenotype correlations in larger cohorts and of the possible clinical effect of MYH8 variants on the risk of cardiac tumorigenesis.
Drs. Morita and Nagai also ask intriguing questions about the potential role of MYH8 in the development of the heart. Echocardiography and electrocardiography have not yet revealed congenital malformations in Family 1, 2, or 3. However, more detailed analyses are ongoing, and we concur with regard to the importance of direct experimentation to determine the contributions of MYH8 to cardiogenesis. We note that, in conformance to the policy of the Journal, the numbering of the families described in our report was changed from that used in previous reports,2 so that correlating the clinical findings in our report with those in the earlier reports can be confusing. The ventriculogram from family member II-7 (Family 1, or YK) in Figure 1C of the article1 shows a similar image from a frame cut from cine film of the same cardiac myxoma shown in an earlier description of this proband.2 Chaudron et al.2 showed an image of the face of family member II-7 that bears a striking similarity to the photograph in our report (Figure 1B1) of her daughter (III-19), who also has the Carney complex and the trismus–pseudocamptodactyly syndrome.
Stratakis and colleagues misread our study. Although the use of precise terminology is important, we did not suggest that all patients with the trismus–pseudocamptodactyly syndrome have a Carney complex variant. Rather, we reported that some unusual patients with typical Carney complex findings also have the trismus–pseudocamptodactyly syndrome, and we termed these combined disorders a Carney complex variant. The typical Carney complex exhibits markedly variable expressivity,3,4,5 and the only feature that occurs nearly uniformly is spotty pigmentation. Among the myriad other findings that occasionally occur, some of the more frequent ones are cardiac, cutaneous, and palpebral myxomas as well as endocrine syndromes such as acromegaly. All these cardiac, dermatologic, neoplastic, and endocrine manifestations were seen and reported in the family described with the variant Carney complex.1,2 We encourage caution when analyzing data from previously established Carney complex databases to identify persons with this rare variant. Such a retrospective review is likely to be insensitive, because the diagnosis of pseudocamptodactyly (in contrast to camptodactyly) requires a focused evaluation of the patient with particular physical examination maneuvers. Identification of the trismus–pseudocamptodactyly syndrome in these cohorts with the Carney complex requires that specifically trained physicians reevaluate them prospectively.
Craig T. Basson, M.D., Ph.D.
Mark Veugelers, Ph.D.
Deborah A. McDermott, M.S.
Weill Medical College of Cornell University
New York, NY 10021
ctbasson@med.cornell.edu
References
Veugelers M, Bressan M, McDermott DA, et al. Mutation of perinatal myosin heavy chain associated with a Carney complex variant. N Engl J Med 2004;351:460-469.
Chaudron JM, Jacques JM, Heller FR, Cheron P, Luwaert R. The myxoma syndrome: an unusual entity: a family study. Eur Heart J 1992;13:569-573.
Stratakis CA, Carney JA, Lin JP, et al. Carney complex, a familial multiple neoplasia and lentiginosis syndrome: analysis of 11 kindreds and linkage to the short arm of chromosome 2. J Clin Invest 1996;97:699-705.
Casey M, Mah C, Merliss AD, et al. Identification of a novel genetic locus for familial cardiac myxomas and Carney complex. Circulation 1998;98:2560-2566.
Veugelers M, Wilkes D, Burton KA, et al. Comparative PRKAR1A genotype-phenotype analyses in humans with Carney complex and prkar1a haploinsufficient mice. Proc Natl Acad Sci U S A 2004;101:14222-14227.