FGF23-骨软化

n engl j med 348;17 www.nejm.org april 24, 2003 The new england journal of medicine 1703 editorials Pediatric Cardiomyopathy — A Long Way to Go Arnold Strauss, M.D., and James E. Lock, M.D. Improvements in the treatment of congenital heart disease are among the most impressive medical achievements of the second half of the 20th centu- ry. In 1950, patent ductus arteriosus and aortic co- arctation were the only correctable lesions, and the likelihood that an infant who received a diagnosis of heart disease in the 1960s would survive the first year of life was only 60 percent, whether treated medically or surgically. 1 Between 1979 and 1997, infant mortality from heart disease declined by 39 percent, 2 and survival rates continue to improve. In many centers, one-year survival rates for infants un- dergoing heart surgery now exceed 95 percent. De- spite these striking advances in treatment, the ge- netic causes of structural heart disease have only begun to be identified in the past 10 years. 3 The results of the treatment of cardiomyopathies in children stand in stark contrast to the successes with the treatment of congenital heart disease. The availability of sophisticated medical management has not yet altered the death rate or the need for transplantation in these children. 4 Almost 40 per- cent of children with symptoms of cardiomyopathy ultimately die of the condition or require cardiac transplantation, and this percentage has remained unaltered by decades of medical research. 5,6 In the face of this lack of therapeutic progress, in this is- sue of the Journal, Nugent et al. 7 and Lipshultz et al. 8 approach the problem of pediatric cardiomyopa- thies from an epidemiologic point of view, defining the scope of the problem and providing important insights that may well guide future therapies. There are several major findings of these two el- egant studies. First, they used different ascertain- ment procedures to document an annual incidence of pediatric cardiomyopathy between 1.13 and 1.24 cases per 100,000 children in regions as geographi- cally diverse as the American Southwest, the Amer- ican Northeast, and the Australian continent. These rates are higher than those reported in prior series. 9 Second, both studies prove that the highest in- cidence of pediatric cardiomyopathy is in the first year of life, with almost half of all cases ascertained by this age, an incidence that is 8 to 12 times as high as that at older ages. Awareness of this result should prompt early diagnostic evaluation in infants with signs and symptoms of congestive heart failure (di- lated cardiomyopathy) and a family history of car- diomyopathy. A second peak occurs in adolescence. Third, both reports demonstrate racial and eth- nic differences in incidence, with higher incidences among black and Hispanic children than among white children in the United States and a higher in- cidence among indigenous children than nonindig- enous children in Australia. These differences sug- gest that genetic or environmental factors, such as susceptibility to viral infections or exposure to tox- ins, can alter the incidence. Fourth, both studies found a significant differ- ence in the incidence according to sex. The reason for this difference is that mutations in the dystro- phin gene (in the case of Duchenne’s and Becker’s muscular dystrophies) and the tafazzin or G4.5 gene (in the case of the Barth syndrome), which are lo- cated on the X chromosome, are relatively common causes of cardiomyopathy in boys. Fifth, both reports emphasize the large familial component of cardiomyopathy, which represents 9 percent (42 of 467 cases) 9 to 20 percent 8 of cases. These must be minimal estimates, because there was no consistent evaluation of family members. These results and similar findings in many other studies 10,11 emphasize the major role that genetic causes have in the pathogenesis of cardiomyopathy, in both adults and children. On the basis of these results, we would recommend that first-degree rel- Downloaded from www.nejm.org on July 11, 2010 . Copyright © 2003 Massachusetts Medical Society. All rights reserved. The new england journal of medicine 1704 n engl j med 348;17 www.nejm.org april 24, 2003 atives of children with cardiomyopathies undergo clinical, echocardiographic, and laboratory evalu- ation. These studies have some important limitations. A minority of specific causes are reported; 57 to 68 percent of cases are described as idiopathic or un- classified. Among the remaining cases, the Ameri- can study reports a specific diagnosis in only 17.5 percent, including 2 percent with documented my- ocarditis and 3 percent with probable myocarditis. The Australian group reports an overall incidence of confirmed or probable myocarditis of 24 percent. This discrepancy is distressing, considering that both groups used the Dallas criteria to make this pathological diagnosis. As was the case in many previous studies, the diagnosis of myocarditis may be subjective, depending on who examines the sam- ple. Alternatively, the difference may be explained by differences in susceptibility to viral infection. Neither group reports specific viral causes of my- ocarditis. The diagnosis of viral myocarditis relies on serologic, culture, polymerase-chain-reaction (PCR), and pathological criteria. We recommend that a careful search for viral infection, with the use of cardiac biopsy and PCR analysis, be considered in all patients with dilated cardiomyopathy. A second limitation is that the authors rely on the World Health Organization’s functional cate- gorization of dilated, hypertrophic, and restrictive cardiomyopathy. Although this classification is helpful in the assessment of possible causes, the clinical course, and treatment, further studies to de- termine the underlying causes are clearly necessary. Finally, minimal outcome data are reported: the U.S. group reported a two-year survival rate of 83 per- cent overall, with an additional 7 percent of patients undergoing transplantation, and the Australian group reported that 3.5 percent of cases were diag- nosed initially at autopsy. Clearly, longer follow-up of these nearly 800 children is necessary to help us understand the risks and outcomes over time and to tease out differences in outcome according to functional and etiologic classifications. These and other recent studies prompt two ques- tions: Why have the childhood cardiomyopathies been so resistant to advances in biomedical under- standing and treatments, and how can we material- ly improve this outcome? In our view, the key to an understanding of these disorders is the realization that many cases have underlying genetic causes. Environmental toxins such as cardiotoxic drugs, nutritional and trace-element deficiencies, maternal diabetes, and infectious agents are known causes, but these account for a minority of cases of cardio- myopathy. Nonetheless, these causes of cardiomy- opathy are treatable, and the underlying dysfunction is usually reversible. Much of cardiomyopathy is familial, 8,9 suggest- ing that there are multiple genetic causes. Over the past 20 years, mutations in more than 30 specific genes have been implicated, including sarcomeric proteins such as the myosin heavy chain, myosin- binding proteins, and troponins in hypertrophic cardiomyopathy and cytoskeletal proteins such as dystrophin, desmin, taffazin, lamin, titin, and ac- tin in dilated cardiomyopathy. Mutations in calci- um-metabolizing genes 12 and cell-signaling mol- ecules such as adenosine monophosphate–activated protein kinase also cause cardiomyopathy. 13 In ad- dition, mutations in enzymes and transporters es- sential for myocardial energy production in mito- chondria, such as the fatty-acid–oxidation enzymes, the carnitine transporter, and components of the respiratory-chain oxidative phosphorylation path- way, have been documented to cause cardiomyop- athy. In a few instances, such as those involving deficiencies of the carnitine transporter and fatty- acid–oxidation enzymes, specific treatments reverse the cardiomyopathy. 14,15 This outcome proves that an understanding of the specific genetic cause of cardiomyopathy can result in specific curative treat- ments, a potential paradigm for the future. In the current era of genomics and proteomics, discover- ing the genetic causes of pediatric and adult cardio- myopathy is becoming increasingly simple and rap- id, providing hope that directed therapies can be developed. The current treatment for cardiomyopathy is usually transplantation. Although the rates of long- term survival with the use of immunosuppression are impressive, cardiac transplantation is unlikely to result in a normal life expectancy in children with cardiomyopathy. Recent findings suggest that nov- el therapies may be on the horizon. For example, several studies show that stem cells can be isolated, amplified in culture, and manipulated to differenti- ate into cardiomyocytes. After injection or implan- tation, small numbers of such cells are incorporated into functioning myocardium, raising the tanta- lizing possibility that stem-cell therapy may some- day be used to reverse myocardial dysfunction. In addition, a recent report indicates that zebrafish myocardium 16 can regenerate. As we come to un- derstand the mechanisms that allow the regulation Downloaded from www.nejm.org on July 11, 2010 . Copyright © 2003 Massachusetts Medical Society. All rights reserved. n engl j med 348;17 www.nejm.org april 24, 2003 editorials 1705 of regeneration in myocardium, treatment through the induction of regeneration may prove feasible, especially in patients with postinfectious and toxic cardiomyopathy. From the Department of Pediatrics, Vanderbilt University School of Medicine, Nashville (A.S.); and the Department of Cardiology, Children’s Hospital, Harvard Medical School, Boston (J.E.L.). 1. Report of the New England Regional Infant Cardiac Program. Pediatrics 1980;65:375-461. 2. Boneva RS, Botto LD, Moore CA, Yang Q, Correa A, Erickson JD. Mortality associated with congenital heart defects in the United States: trends and racial disparities, 1979-1997. Circulation 2001; 103:2376-81. 3. Olson EN, Srivastava D. Molecular pathways controlling heart development. Science 1996;272:671-6. 4. Kumar K, Thatai D, Saxena A, et al. Pediatric dilated cardiomy- opathy: prognosis in a developing nation is comparable to devel- oped nations. Int J Cardiol (in press). 5. Lipshultz SE. Ventricular dysfunction clinical research in infants, children and adolescents. Prog Pediatr Cardiol 2000;12:1-28. 6. Bilgic A, Ozbarlas N, Ozkutlu S, Ozer S, Ozme S. Cardiomyopa- thies in children: clinical, epidemiological and prognostic evalua- tion. Jpn Heart J 1990;31:789-97. 7. Nugent AW, Daubeney PEF, Chondros P, et al. The epidemiology of childhood cardiomyopathy in Australia. N Engl J Med 2003;348: 1639-46. 8. Lipshultz SE, Sleeper LA, Towbin JA, et al. The incidence of pediatric cardiomyopathy in two regions of the United States. N Engl J Med 2003;348:1647-55. 9. Arola A, Jokinen E, Ruuskanen O, et al. Epidemiology of idio- pathic cardiomyopathies in children and adolescents: a nationwide study in Finland. Am J Epidemiol 1997;146:385-93. 10. Michels VV, Moll PP, Miller FA, et al. The frequency of familial dilated cardiomyopathy in a series of patients with idiopathic dilated cardiomyopathy. N Engl J Med 1992;326:77-82. 11. Kelly DP, Strauss AW. Inherited cardiomyopathies. N Engl J Med 1994;330:913-9. 12. Schmitt JP, Kamisago M, Asahi M, et al. Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban. Science 2003;299:1410-3. 13. Arad M, Benson DW, Perez-Atayde AR, et al. Constitutively active AMP kinase mutations cause glycogen storage disease mim- icking hypertrophic cardiomyopathy. J Clin Invest 2002;109:357-62. 14. Bennett MJ, Rinaldo P, Strauss AW. Inborn errors of mitochon- drial fatty acid oxidation. Crit Rev Clin Lab Sci 2000;37:1-44. 15. Strauss AW. Defects of mitochondrial proteins and pediatric heart disease. Prog Pediatr Cardiol 1996;6:83-90. 16. Poss KD, Wilson LG, Keating MT. Heart regeneration in zebra- fish. Science 2002;298:2188-90. Copyright © 2003 Massachusetts Medical Society. Oncogenic Osteomalacia — A Complex Dance of Factors Thomas O. Carpenter, M.D. Oncogenic osteomalacia has fascinated physiolo- gy-minded physicians for decades. The traditional name for this peculiar disorder connotes its classi- fication as a paraneoplastic phenomenon. Such a characterization is a bit off the mark, however, in that the involved “neoplasm” is often (but not al- ways) of limited clinical significance apart from its causal role in the musculoskeletal disease. Tumors responsible for oncogenic osteomalacia are usually benign rather than invasive, whereas generalized, debilitating osteomalacia and rickets are the im- portant clinical problems for the patient. The assay for the measurement of circulating levels of fibro- blast growth factor 23 (FGF-23), the development of which is described by Jonsson et al. 1 in this issue of the Journal , may prove to be useful in the investiga- tion and management of oncogenic osteomalacia. The clinical presentation of oncogenic osteoma- lacia is reminiscent of that of the more common disorder X-linked hypophosphatemia, 2 which has been studied intensively and serves as the prototyp- ic hypophosphatemic disorder. Oncogenic osteo- malacia, like X-linked hypophosphatemia, is mani- fested by decreased mineralization of newly formed bone and the clinical findings of osteomalacia. In growing children, rachitic deformities of the growth plates occur. A useful clinical distinction between the two disorders is the patient’s age at the onset of the disease: oncogenic osteomalacia is an acquired phenotype, whereas X-linked hypophosphatemia tends to become evident during the second year of life. There are exceptions to this generalization: a later onset of X-linked and autosomal dominant hy- pophosphatemic rickets does occur. Patients with oncogenic osteomalacia frequently present with fractures and more severe bone pain than that which occurs in X-linked hypophosphatemia and often report muscle weakness — an unusual symptom in patients with X-linked hypophosphatemia. The characteristic hypophosphatemia results from an excessive renal loss of phosphate. The se- rum calcium level is usually normal, but mild hypo- calcemia has been described. Elevations of serum alkaline phosphatase activity are typical, and the se- verity of this abnormality can exceed that seen in X-linked hypophosphatemia. Serum levels of para- thyroid hormone have been variably reported as low clinical presentation Downloaded from www.nejm.org on July 11, 2010 . Copyright © 2003 Massachusetts Medical Society. All rights reserved.