THE NEW ENGLAND JOURNAL OF MEDICINE
1258
of neovascularization in immature eyes. Several investigators in this country and abroad have been attempting to clarify the whole pathogenesis of retrolental fibroplasia for over 20 years. We all hope to be able to avert cases of the disorder in the future so that this condition will again become extremely rare. Abington, PA 19001
BRIAN ALTMAN, M.D. 1400 Old York Rd.
The above letter was referred to Dr. Schwartz, who offers the following reply:
To the Editor: My comment, "The longer survival of premature infants through the use of oxygen has led to the increase in retrolental fibroplasia..., " was used in a historical context only. Now we are all fully aware that retrolental fibroplasia can and does occur in fullterm infants, and I am glad that Dr. Altman has emphasized this point. Boston, MA 02111
BERNARD SCHWARTZ, M.D., PH.D. New England Medical Center Hospital
GENE MAPPING IN THALASSEMIA
To the Editor: We are pleased to see that detection of specific human globin-gene deletions by restriction endonuclease mapping of the mutants hereditary persistence of fetal hemoglobin and 6/ thalassemia, described by us several months ago,' has been so quickly applied to the prenatal detection of these disorders.2 We should like to add a cautionary note not adequately stressed by the authors. There are substantial differences between the results presented in the Journal article and ours, which may complicate the use of this technic for prenatal diagnosis. For example, our homozygote for /B3 thalassemia has two,-like Eco RI fragments, one of which appears to be unique to this patient, whereas the 6/ homozygote described in the j7ournal has no detectable $-like fragments. Similarly, our homozygote for hereditary persistence of fetal hemoglobin has one ,B-like fragment, whereas the two patients described by Orkin et al.2 have none. This apparent heterogeneity of gene defects in these syndromes, and perhaps in the a and dl thalassemias as well, could lead to difficulties in recognizing the specific defect in DNA in homozygotes at risk unless other homozygotes in the family are also available for study and demonstrate gene deletion, as in the 6/3 thalassemia case described in the journal. Alternatively, heterozygotes with unique new DNA bands similar to those seen in our case of 6/ thalassemia' could permit a correct prenatal diagnosis. If only normal restriction patterns are obtained from other family members in a given case, it is possible that affected homozygous fetuses will be undetected by restriction enzyme mapping. To date, the more common /3+ and /3" thalassemias have been in this category; they have not been associated with detectable alterations in restriction fragment patterns in studies in our laboratory. As discussed in the editorial accompanying the j3ournal article,3 it is possible that accurate prenatal diagnosis of these and other inherited disorders not necessarily associated with detectable gene deletion will also be achieved by restriction enzyme mapping if the precise nucleotide change in these diseases can be identified. J. GREGORY MEARS, M.D. FRANCEsCO RAMIREZ, PH.D. DAVID LEIBOWITZ, M.D. Boston, MA 02115
ARTHUR BANK, M.D. Children's Hospital Medical Center
I. Mears JG, Ramirez J, Leibowitz D, et al: Changes in restricted human cellular DNA fragments containing globin gene sequences in thalassemias and related disorders. Proc Natl Acad Sci USA 75:1222-1226, 1978 2. Orkin SH, Alter BP, Altay C, et al: Application of endonuclease mapping to the analysis and prenatal diagnosis of thalassemias caused by globin-gene deletion. N Engl J Med 299:166-172, 1978 3. Nienhuis AW: Mapping the human genome. N Engl J Med 299:195-196, 1978
Nov. 30, 1978
The above letter was referred to the authors of the article in question, one of whom offers the following reply: To the Editor: Mears et al. suggest that molecular heterogeneity in the underlying defects in thalassemia syndromes may complicate prenatal diagnosis by restriction endonuclease mapping of cellular DNA. Our report' dealt specifically only with three rare homozygous conditions, bfl thalassemia, hereditary persistence of fetal hemoglobin and a thalassemia, each of which has been associated with gene deletion in all cases studied to date by either conventional liquid hybridization or the newer mapping technics. The cases of bfl thalassemia and hereditary persistence of fetal hemoglobin studied by Mears et al.2 also reveal gene deletion and display residual ,B-like material. Indeed, we have examined a series of patients carrying bf thalassemic lesions and observed at least two types3: one associated with Bfl deletion and another with the appearance of a new ,8-like fragment, similar to that reported by Mears et al.2 Thus, we are confident that heterogeneity in the extent of gene deletion in these f-deletion syndromes does exist. Nevertheless, molecular heterogeneity of this kind in gene deletion does not limit the ability of restriction mapping to arrive at the correct diagnosis in a fetus at risk since the absence of normal globin-specific fragments would be found only in the homozygote. If any examples of homozygous a thalassemia (hydrops fetalis) or 6fl thalassemia are found to be associated with the presence of completely nonfunctional, but structurally normal, respective globingene regions, this conclusion would naturally have to be modified. To date, however, there is no evidence that such an association ever occurs. In agreement with Mears et al. we find that most f+ and f0 thalassemic DNA's have grossly normal restriction patterns. Nonetheless, even in ,B0 thalassemia there is molecular heterogeneity since a subgroup of patients has been identified in which a structurally abnormal f-gene region is seen.3 Further work is obviously necessary to extend the new mapping technics to the prenatal diagnosis of more common thalassemias. STUART H. ORKIN, M.D. Children's Hospital Medical Center Boston, MA 02115 Sidney Farber Cancer Center 1. Orkin SH, Alter BP, Altay C, et al: Application of endonuclease mapping to the analysis and prenatal diagnosis of thalassemias caused by globin-gene deletion. N Engl J Med 299:166-172, 1978 2. Mears JG, Ramirez F, Leibowitz D, et al: Changes in restricted human cellular DNA fragments containing globin gene sequences in thalassemias and related disorders. Proc Natl Acad Sci USA 75:1222-1226, 1978 3. Orkin SH, Old J, Lazarus H, et al: Alterations in globin gene organization in thalassemia syndromes. To be presented at the 21st annual meeting of the American Society of Hematology, New Orleans, December 2-5, 1978
PSYCHIATRIC CARE BY FOREIGN MEDICAL GRADUATES To the Editor: Two recent articles in the Journal were devoted to foreign medical graduates.',2 Perlman et al.2 express concern that Medicaid patients obtain psychiatric care from such graduates more often than non-Medicaid patients. The authors quote studies showing that foreign medical graduates perform less well than graduates of United States schools on specialty boards and intraining examinations, implying by innuendo that the care rendered by the former is inferior to that of the latter. We object to stigmatizing foreign graduates as a group on the basis of their examination grades. To our knowledge, there are no data indicating that the quality of medical care correlates with grades.3 It is not surprising that foreign medical graduates perform less well on examinations than United States medical graduates. They are not familiar with the type of questions to which American medical students are being repeatedly exposed during their studies. They are also handicapped by language. In spite of these handicaps, many succeeded in integrating into American medicine.4,5
The New England Journal of Medicine Downloaded from nejm.org at SANTA CRUZ (UCSC) on November 12, 2015. For personal use only. No other uses without permission. From the NEJM Archive. Copyright © 2010 Massachusetts Medical Society. All rights reserved.
1258
of neovascularization in immature eyes. Several investigators in this country and abroad have been attempting to clarify the whole pathogenesis of retrolental fibroplasia for over 20 years. We all hope to be able to avert cases of the disorder in the future so that this condition will again become extremely rare. Abington, PA 19001
BRIAN ALTMAN, M.D. 1400 Old York Rd.
The above letter was referred to Dr. Schwartz, who offers the following reply:
To the Editor: My comment, "The longer survival of premature infants through the use of oxygen has led to the increase in retrolental fibroplasia..., " was used in a historical context only. Now we are all fully aware that retrolental fibroplasia can and does occur in fullterm infants, and I am glad that Dr. Altman has emphasized this point. Boston, MA 02111
BERNARD SCHWARTZ, M.D., PH.D. New England Medical Center Hospital
GENE MAPPING IN THALASSEMIA
To the Editor: We are pleased to see that detection of specific human globin-gene deletions by restriction endonuclease mapping of the mutants hereditary persistence of fetal hemoglobin and 6/ thalassemia, described by us several months ago,' has been so quickly applied to the prenatal detection of these disorders.2 We should like to add a cautionary note not adequately stressed by the authors. There are substantial differences between the results presented in the Journal article and ours, which may complicate the use of this technic for prenatal diagnosis. For example, our homozygote for /B3 thalassemia has two,-like Eco RI fragments, one of which appears to be unique to this patient, whereas the 6/ homozygote described in the j7ournal has no detectable $-like fragments. Similarly, our homozygote for hereditary persistence of fetal hemoglobin has one ,B-like fragment, whereas the two patients described by Orkin et al.2 have none. This apparent heterogeneity of gene defects in these syndromes, and perhaps in the a and dl thalassemias as well, could lead to difficulties in recognizing the specific defect in DNA in homozygotes at risk unless other homozygotes in the family are also available for study and demonstrate gene deletion, as in the 6/3 thalassemia case described in the journal. Alternatively, heterozygotes with unique new DNA bands similar to those seen in our case of 6/ thalassemia' could permit a correct prenatal diagnosis. If only normal restriction patterns are obtained from other family members in a given case, it is possible that affected homozygous fetuses will be undetected by restriction enzyme mapping. To date, the more common /3+ and /3" thalassemias have been in this category; they have not been associated with detectable alterations in restriction fragment patterns in studies in our laboratory. As discussed in the editorial accompanying the j3ournal article,3 it is possible that accurate prenatal diagnosis of these and other inherited disorders not necessarily associated with detectable gene deletion will also be achieved by restriction enzyme mapping if the precise nucleotide change in these diseases can be identified. J. GREGORY MEARS, M.D. FRANCEsCO RAMIREZ, PH.D. DAVID LEIBOWITZ, M.D. Boston, MA 02115
ARTHUR BANK, M.D. Children's Hospital Medical Center
I. Mears JG, Ramirez J, Leibowitz D, et al: Changes in restricted human cellular DNA fragments containing globin gene sequences in thalassemias and related disorders. Proc Natl Acad Sci USA 75:1222-1226, 1978 2. Orkin SH, Alter BP, Altay C, et al: Application of endonuclease mapping to the analysis and prenatal diagnosis of thalassemias caused by globin-gene deletion. N Engl J Med 299:166-172, 1978 3. Nienhuis AW: Mapping the human genome. N Engl J Med 299:195-196, 1978
Nov. 30, 1978
The above letter was referred to the authors of the article in question, one of whom offers the following reply: To the Editor: Mears et al. suggest that molecular heterogeneity in the underlying defects in thalassemia syndromes may complicate prenatal diagnosis by restriction endonuclease mapping of cellular DNA. Our report' dealt specifically only with three rare homozygous conditions, bfl thalassemia, hereditary persistence of fetal hemoglobin and a thalassemia, each of which has been associated with gene deletion in all cases studied to date by either conventional liquid hybridization or the newer mapping technics. The cases of bfl thalassemia and hereditary persistence of fetal hemoglobin studied by Mears et al.2 also reveal gene deletion and display residual ,B-like material. Indeed, we have examined a series of patients carrying bf thalassemic lesions and observed at least two types3: one associated with Bfl deletion and another with the appearance of a new ,8-like fragment, similar to that reported by Mears et al.2 Thus, we are confident that heterogeneity in the extent of gene deletion in these f-deletion syndromes does exist. Nevertheless, molecular heterogeneity of this kind in gene deletion does not limit the ability of restriction mapping to arrive at the correct diagnosis in a fetus at risk since the absence of normal globin-specific fragments would be found only in the homozygote. If any examples of homozygous a thalassemia (hydrops fetalis) or 6fl thalassemia are found to be associated with the presence of completely nonfunctional, but structurally normal, respective globingene regions, this conclusion would naturally have to be modified. To date, however, there is no evidence that such an association ever occurs. In agreement with Mears et al. we find that most f+ and f0 thalassemic DNA's have grossly normal restriction patterns. Nonetheless, even in ,B0 thalassemia there is molecular heterogeneity since a subgroup of patients has been identified in which a structurally abnormal f-gene region is seen.3 Further work is obviously necessary to extend the new mapping technics to the prenatal diagnosis of more common thalassemias. STUART H. ORKIN, M.D. Children's Hospital Medical Center Boston, MA 02115 Sidney Farber Cancer Center 1. Orkin SH, Alter BP, Altay C, et al: Application of endonuclease mapping to the analysis and prenatal diagnosis of thalassemias caused by globin-gene deletion. N Engl J Med 299:166-172, 1978 2. Mears JG, Ramirez F, Leibowitz D, et al: Changes in restricted human cellular DNA fragments containing globin gene sequences in thalassemias and related disorders. Proc Natl Acad Sci USA 75:1222-1226, 1978 3. Orkin SH, Old J, Lazarus H, et al: Alterations in globin gene organization in thalassemia syndromes. To be presented at the 21st annual meeting of the American Society of Hematology, New Orleans, December 2-5, 1978
PSYCHIATRIC CARE BY FOREIGN MEDICAL GRADUATES To the Editor: Two recent articles in the Journal were devoted to foreign medical graduates.',2 Perlman et al.2 express concern that Medicaid patients obtain psychiatric care from such graduates more often than non-Medicaid patients. The authors quote studies showing that foreign medical graduates perform less well than graduates of United States schools on specialty boards and intraining examinations, implying by innuendo that the care rendered by the former is inferior to that of the latter. We object to stigmatizing foreign graduates as a group on the basis of their examination grades. To our knowledge, there are no data indicating that the quality of medical care correlates with grades.3 It is not surprising that foreign medical graduates perform less well on examinations than United States medical graduates. They are not familiar with the type of questions to which American medical students are being repeatedly exposed during their studies. They are also handicapped by language. In spite of these handicaps, many succeeded in integrating into American medicine.4,5
The New England Journal of Medicine Downloaded from nejm.org at SANTA CRUZ (UCSC) on November 12, 2015. For personal use only. No other uses without permission. From the NEJM Archive. Copyright © 2010 Massachusetts Medical Society. All rights reserved.
